C.7006A>T
Case#: 31
DiseaseAssertion: Hemophilia A
FamilyInfo: Positive
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Moderate
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.7006A>T (p.Ile2317Phe)
ClinVar: NA
CAID: CA414896884
gnomAD: Not reported
c.1682delA
Case#: 2
DiseaseAssertion: Hemophilia A
FamilyInfo: Sporadic
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.1682del (p.Asp561ValfsTer2)
ClinVar: NA
CAID: CA1139532041
gnomAD: Not reported
c.5159C>T
Case#: 24
DiseaseAssertion: Hemophilia A
FamilyInfo: Positive
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Mild
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.5159C>T (p.Ala1701Val)
ClinVar: NA
CAID: CA414913679
gnomAD: Not reported
c.248C>G
Case#: 12
DiseaseAssertion: Hemophilia A
FamilyInfo: Positive
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Mild
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.248C>G (p.Pro83Arg)
ClinVar: NA
CAID: CA10568618
gnomAD: MAF for Pro83Arg in the Ashkenazi Jewish population 0.0001335<br>https://gnomad.broadinstitute.org/variant/X-154227771-G-C?dataset=gnomad_r2_1
c.1487C>G
Case#: 20
DiseaseAssertion: Hemophilia A
FamilyInfo: Sporadic
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.1487C>G (p.Pro477Arg)
ClinVar: NA
CAID: CA414912766
gnomAD: Not reported
166
Case#: 166, male, 12 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.4379delA
LegacyVariant:
ClinVar: No
CAID: CA255151
gnomAD:
26
Case#: 26, male, 13 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6976C>T
LegacyVariant:
ClinVar: 10085
CAID: CA255007
gnomAD:
36
Case#: 36, male, 10 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.387G>C
LegacyVariant:
ClinVar: No
CAID: CA414919866
gnomAD:
139
Case#: 139, male, 17 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.dup exons7_22
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
115
Case#: 115, male, 37 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.1271+1G>A
LegacyVariant:
ClinVar: 811704
CAID: CA414915622
gnomAD:
13
Case#: 13, male, 24 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.1861C>T
LegacyVariant:
ClinVar: No
CAID: CA414910596
gnomAD:
16
Case#: 16, male, 22 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.2404C>T
LegacyVariant:
ClinVar: No
CAID: CA414901774
gnomAD:
161
Case#: 161, male, 8 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 1.5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.3637delA
LegacyVariant:
ClinVar: No
CAID: CA255146
gnomAD:
88
Case#: 88, male, 29 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 2%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6406G>A
LegacyVariant:
ClinVar: No
CAID: CA414899430
gnomAD:
80
Case#: 80, male, 52 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 10.9%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.5707G>A
LegacyVariant:
ClinVar: No
CAID: CA414907751
gnomAD:
56
Case#: 56, male, 12 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 29%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.1834C>T
LegacyVariant:
ClinVar: 10236
CAID: CA255129
gnomAD:
69
Case#: 69, male, 11 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 1.1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.5321A>T
LegacyVariant:
ClinVar: No
CAID: CA414910719
gnomAD:
34
Case#: 34, male, 25 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.382T>C
LegacyVariant:
ClinVar: 811825
CAID: CA414919878
gnomAD:
75
Case#: 75, male, 14 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 16.5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.5545T>A
LegacyVariant:
ClinVar: No
CAID: CA414908552
gnomAD:
179
Case#: 179, male, 11 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.del exon14
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
146
Case#: 146, male, 13 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.209_212delTTGT
LegacyVariant:
ClinVar: No
CAID: CA255050
gnomAD:
61
Case#: 61, male, 7 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.2066T>C
LegacyVariant:
ClinVar: No
CAID: CA414909145
gnomAD:
132
Case#: 132, male, 28 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 2.7%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.4379dupA
LegacyVariant:
ClinVar: No
CAID: CA645292749
gnomAD:
7
Case#: 7, male, 8 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.1063C>T
LegacyVariant:
ClinVar: 10139
CAID: CA255031
gnomAD:
45
Case#: 45, male, 75 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 6.5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.1172G>A
LegacyVariant:
ClinVar: 10111
CAID: CA120918
gnomAD:
157
Case#: 157, male, 30 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 1.2%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.3637delA
LegacyVariant:
ClinVar: No
CAID: CA255146
gnomAD:
1
Case#: 1, male, 30 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.36C>A
LegacyVariant:
ClinVar: No
CAID: CA414920668
gnomAD:
84
Case#: 84, male, 48 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.5821A>C
LegacyVariant:
ClinVar: No
CAID: CA414906679
gnomAD:
20
Case#: 20, male, 36 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.5953C>T
LegacyVariant:
ClinVar: 10300
CAID: CA255191
gnomAD:
A 68-year-old male was diagnosed with severe HEMA in early childhood
Case#: 68 year old male
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Mother was a carrier and brother also suffered from severe Hemophilia A
ParentalTesting: No
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 0.001%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: Whole exome sequencing was performed and subsequently analyzed
Gene: F8
Variant: NM_000132.3:c.5411_5413del
LegacyVariant:
ClinVar: No
CAID: NA
gnomAD:
Preconception Carrier Screening by Genome Sequencing: Results from the Clinical Laboratory
PMID: 29754767
Gene: F8
HGNC: 3546
InsufficientEvidence: This article mentions a F8 variant however does not have a detailed case report for a proband
035–2003
Case#: 035-2003
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.4825dupA
LegacyVariant:
ClinVar: No
CAID: CA255152
gnomAD:
028–1002
Case#: 028-1002
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant:
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
071–2029
Case#: 071-2029
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1697T>A
LegacyVariant:
ClinVar: No
CAID: CA414911721
gnomAD:
035–2007
Case#: 035-2007
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1963_1964insT
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
002–2017
Case#: 002-2017
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.941C>T
LegacyVariant:
ClinVar: No
CAID: CA414917829
gnomAD:
071–2010
Case#: 071-2010
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1208A>C
LegacyVariant:
ClinVar: No
CAID: CA414916134
gnomAD:
001–1060
Case#: 001-1060
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.686C>G
LegacyVariant:
ClinVar: No
CAID: CA414919141
gnomAD:
047–1020
Case#: 047-1020
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 1% < FVIII:C < 5%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.3169G>A
LegacyVariant:
ClinVar: No
CAID: CA255144
gnomAD:
091–2009
Case#: 091-2009
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.2681delG
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
003–2024
Case#: 003-2024
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.5399G>A
LegacyVariant:
ClinVar: No
CAID: CA255162
gnomAD:
071–1036
Case#: 071-1036
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 1% < FVIII:C < 5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant:
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
060–2010
Case#: 060-2010
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1834C>T
LegacyVariant:
ClinVar: No
CAID: CA255129
gnomAD:
020–2024
Case#: 020-2024
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.437A>C
LegacyVariant:
ClinVar: No
CAID: CA414919724
gnomAD:
001–2027
Case#: 001-2027
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1869_1870delG
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
015–2003
Case#: 015-2003
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.3637delA
LegacyVariant:
ClinVar: No
CAID: CA255146
gnomAD:
020–2006
Case#: 020-2006
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1492G>A
LegacyVariant:
ClinVar: No
CAID: CA255109
gnomAD:
035–2022
Case#: 035-2022
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.5954G>A
LegacyVariant:
ClinVar: No
CAID: CA414905715
gnomAD:
020–2027
Case#: 020-2027
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.5253A>C
LegacyVariant:
ClinVar: No
CAID: CA414911240
gnomAD:
091–2008
Case#: 091-2008
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 1% < FVIII:C < 5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.142A>G
LegacyVariant:
ClinVar: No
CAID: CA414920432
gnomAD:
001–2051
Case#: 001-2051
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 1% < FVIII:C < 5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.2134C>A
LegacyVariant:
ClinVar: No
CAID: CA414904092
gnomAD:
042–1001
Case#: 042-1001
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.2144+2A>G
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
UQU-HA35
Case#: UQU-HA35, Male, 2-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: PTT 118.8, Disabled both knees, Severe
CasePreviousTesting: Screened for inversion 22 by inverse PCR, screened for inversion 1 by multiplexed PCR, capillary sequencing (Sanger method) was performed for factor VIII all 26 exons
Gene: F8
Variant: NM_000132.3:c.1835G>C (p.Arg612Pro)
ClinVar: NA
CAID: CA414910775
gnomAD: Not reported
UQU-HB7
Case#: UQU-HB7, Male, 16-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe, Disabled right knee and both ankles , PTT 53.2
CasePreviousTesting: Screened for all factor IX exons by capillary sequencing
Gene: F9
Variant: NM_000133.3(F9):c.880C>T (p.Arg294Ter)
ClinVar: 10587 https://www.ncbi.nlm.nih.gov/clinvar/variation/10587/
CAID: CA255344
gnomAD: Not reported
UQU-HA36
Case#: UQU-HA36, Male, 6-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: PTT 125.4, Severe, Disabled right knees, left elbow, and ankle
CasePreviousTesting: Screened for inversion 22 by inverse PCR, screened for inversion 1 by multiplexed PCR, capillary sequencing (Sanger method) was performed for factor VIII all 26 exons
Gene: F8
Variant: NM_000132.3:c.409A>C (p.Thr137Pro)
ClinVar: NA
CAID: CA414919795
gnomAD: Not reported
Table 1
Case#: Cz6, Italy (Calabria)
DiseaseAssertion: Hemophilia A
FamilyInfo: Sporadic
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVII:C <1%
CasePreviousTesting: Polymerase chain reaction (PCR) analysis, Long PCR for detecting the intron 22 inversion was performed, Direct cycle sequence analysis using the Taq dye-deoxy terminator method
Gene: F8
Variant: NM_000132.3(F8):c.4156C>T (p.Gln1386Ter)
ClinVar: NA
CAID: CA414891965
gnomAD: Not reported
Table 2
Case#: Cz40, Italy (Calabria)
DiseaseAssertion: Hemophilia A
FamilyInfo: Inherited
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVII:C 2.5%
CasePreviousTesting: Polymerase chain reaction (PCR) analysis, Long PCR for detecting the intron 22 inversion was performed, Direct cycle sequence analysis using the Taq dye-deoxy terminator method
Gene: F8
Variant: NM_000132.3:c.1538-18G>A
ClinVar: 811357 https://www.ncbi.nlm.nih.gov/clinvar/variation/811357/
CAID: CA873354114
gnomAD: Not reported
Table 2
Case#: Cz5, Italy (Calabria)
DiseaseAssertion: Hemophilia A
FamilyInfo: Inherited
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVII:C 4%
CasePreviousTesting: Polymerase chain reaction (PCR) analysis, Long PCR for detecting the intron 22 inversion was performed, Direct cycle sequence analysis using the Taq dye-deoxy terminator method
Gene: F8
Variant: NM_000132.3:c.1538-18G>A
ClinVar: 811357 https://www.ncbi.nlm.nih.gov/clinvar/variation/811357/
CAID: CA873354114
gnomAD: Not reported
Table 2
Case#: Cz13, Italy (Calabria)
DiseaseAssertion: Hemophilia A
FamilyInfo: Inherited
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVII:C 4%
CasePreviousTesting: Polymerase chain reaction (PCR) analysis, Long PCR for detecting the intron 22 inversion was performed, Direct cycle sequence analysis using the Taq dye-deoxy terminator method
Gene: F8
Variant: NM_000132.3:c.1538-18G>A
ClinVar: 811357 https://www.ncbi.nlm.nih.gov/clinvar/variation/811357/
CAID: CA873354114
gnomAD: Not reported
Table 1
Case#: Cz7, Italy (Calabria)
DiseaseAssertion: Hemophilia A
FamilyInfo: Sporadic
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVII:C <1%
CasePreviousTesting: Polymerase chain reaction (PCR) analysis, Long PCR for detecting the intron 22 inversion was performed, Direct cycle sequence analysis using the Taq dye-deoxy terminator method
Gene: F8
Variant: NM_000132.3(F8):c.5143C>T (p.Arg1715Ter)
ClinVar: 10267 https://www.ncbi.nlm.nih.gov/clinvar/variation/10267/
CAID: CA255155
gnomAD: Not reported
Table 2
Case#: Cz16, Italy (Calabria)
DiseaseAssertion: Hemophilia A
FamilyInfo: Sporadic
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVII:C 4%
CasePreviousTesting: Polymerase chain reaction (PCR) analysis, Long PCR for detecting the intron 22 inversion was performed, Direct cycle sequence analysis using the Taq dye-deoxy terminator method
Gene: F8
Variant: NM_000132.3:c.1538-18G>A
ClinVar: 811357 https://www.ncbi.nlm.nih.gov/clinvar/variation/811357/
CAID: CA873354114
gnomAD: Not reported
c.6622C>G
Case#: 33
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 21/29/33/15/20/26%, Mild Phenotype, No inhibitors present
CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing
Gene: F8
Variant: NM_000132.3(F8):c.6622C>G (p.Gln2208Glu)
ClinVar: 811219 https://www.ncbi.nlm.nih.gov/clinvar/variation/811219/
CAID: CA414905992
gnomAD: MAF for Gln2208Glu in the Other population 0.0002208<br>https://gnomad.broadinstitute.org/variant/X-154090094-G-C?dataset=gnomad_r2_1
c.1649G>A
Case#: 14
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 27% (Mild Phenotype), No inhibitors present
CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing
Gene: F8
Variant: NM_000132.3(F8):c.1649G>A (p.Arg550His)
ClinVar: 10225 https://www.ncbi.nlm.nih.gov/clinvar/variation/10225/
CAID: CA255115
gnomAD: MAF for Arg550His in European (non-Finnish) population 0.00002442<br> https://gnomad.broadinstitute.org/variant/X-154185335-C-T?dataset=gnomad_r2_1
c.280A>G
Case#: 2
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 32% (Mild Phenotype), No inhibitors present
CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing
Gene: F8
Variant: NM_000132.3(F8):c.280A>G (p.Thr94Ala)
ClinVar: NA
CAID: CA10568603
gnomAD: MAF for Thr94Ala in the European (Non-Finnish) population 0.00001222<br> https://gnomad.broadinstitute.org/variant/X-154225356-T-C?dataset=gnomad_r2_1
c.7031G>C
Case#: 38
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 29%, Mild Phenotype, No inhibitors present
CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing
Gene: F8
Variant: NM_000132.3:c.7031G>C (p.Gly2344Ala)
ClinVar: NA
CAID: CA414896685
gnomAD: Not reported
c.6118T>G
Case#: 29
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 10/8/14%, Mild Phenotype, No inhibitors present
CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing
Gene: F8
Variant: NM_000132.3:c.6118T>G (p.Cys2040Gly)
ClinVar: NA
CAID: CA414904332
gnomAD: Not reported
c.422G>A
Case#: 42
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C 4% (Moderate Phenotype)
CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing
Gene: F9
Variant: NM_000133.4(F9):c.422G>A (p.Cys141Tyr)
ClinVar: 811510 https://www.ncbi.nlm.nih.gov/clinvar/variation/811510/
CAID: CA414438897
gnomAD: Not reported
S8
Case#: S8, Iranian
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Family history of HA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125, HP:0005261
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The F8 gene was directly sequenced for all 26 exons using the Sanger sequencing method. PCR was performed and subsequently analyzed
Gene: F8
Variant: NA
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
S16
Case#: S16, Iranian
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125, HP:0005261
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The F8 gene was directly sequenced for all 26 exons using the Sanger sequencing method. PCR was performed and subsequently analyzed
Gene: F8
Variant: NA
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
A12
Case#: A12
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 28, FVIII:AG = 54, assay discrepancy present (OSA>CSA)
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: Coding region and intron/exon bound-aries of the F8 gene were amplified from all patient samples and directly sequenced using primers
Gene: F8
Variant: NM_000132.4:c.2045T>C
LegacyVariant:
ClinVar: No
CAID: CA414909247
gnomAD:
A16
Case#: A16
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 7, FVIII:AG = 23, assay discrepancy present (OSA>CSA)
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: Coding region and intron/exon bound-aries of the F8 gene were amplified from all patient samples and directly sequenced using primers
Gene: F8
Variant: NM_000132.4:c.5879G>A
LegacyVariant:
ClinVar: No
CAID: CA255019
gnomAD:
9-month old boy was diagnosed with severe haemophilia B
Case1: Male, 9-months at time of diagnosis
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0001933 (Subcutaneous hemorrhage), HP:0007420 (Spontaneous hematomas), HP:0012233 (Intramuscular hematoma), HP:0005261 (Joint hemorrhage)
CaseHPOFreeText: FIX: C <1%, recurrent anaphylactic reactions to FIX (abdominal pain, respiratory arrest, and severe hypotension)
CasePreviousTesting: F9 analysis (revealed a point mutation at exon H)
Gene: F9
Variant: NM_000133.3(F9):c.880C>T (p.Arg294Ter)
LegacyVariant: g 30863 C>T; Arg 248 stop
ClinVar: 10587 https://www.ncbi.nlm.nih.gov/clinvar/variation/10587/
gnomAD: Not reported
Factor VIII: Long-established role in haemophilia A and emerging evidence beyond haemostasis
PMID: 30922616
Gene: F8
HGNC: 3546
InsufficientEvidence: This article is a review, it does not mention any new case reports
PreviouslyPublished
Genetic testing in the probands from two independent Slovenian families identified a novel variant c.3457T>A (Ter1153Lysext*38) in the RPGRORF15. The variant is predicted to disrupt the terminal codon of the RPGRORF15, resulting in a C-terminal extension of the protein by 38 aminoacids ending with a new stop codon. The variant has not been reported in the biomedical literature and is not present in the GnomAD population database (gnomad.broadinstitute.org, accessed on 06.01.2021). Single-nucleotide polymorphism analysis comparing X-chromosomes of the probands is shown in Figure 2C. On the X-chromosome we identified a large block of hemizygous SNPs shared by both probands with an estimated size of 29 megabases, which suggests that observation of an identical variant in two independent families may be due to a founder effect.
Case#: Hadalin_2021_Family_1_Patient_III-1, male, 31 years old at first examination, family origin in Slovenia
CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000545 (Myopia), HP:0008020 (Cone dystrophy), HP:0007663 (Reduced visual acuity), HP:0012230 (Rhegmatogenous retinal detachment), HP:0000603 (Central scotoma), HP:0007814 (Retinal pigment epithelial mottling), HP:0008043 (Retinal arteriolar constriction), HP:0000543 (Optic disc pallor), HP:0030602 (Abnormal fundus autofluorescence imaging), HP:0200070 (Peripheral retinal atrophy), HP:0030465 (Undetectable light-adapted electroretinogram), HP:0000613 (Photophobia), HP:0011504 (Bull's eye maculopathy), HP:0007737 (Bone spicule pigmentation of the retina),
CaseHPOFreeText: The patient received a diagnosis of cone dystrophy. Myopia was present from childhood, while visual loss occurred in the early 30's.
CaseNotHPOs: N/A
CaseNotHPOFreeText: Dark-adapted ERG was normal at the time of the study.
CasePreviousTesting: The patient and an apparently unrelated proband from another family were subjected to whole-exome sequencing.
CaseMethod1: Whole-exome sequencing
CaseMethod2: Haplotype analysis using SNPs on the X chromosome
CaseGenotypingMethod: The patient and a proband from another family not known to be related were subjected to whole-exome sequencing, followed by haplotype analysis using SNPs on the X chromosome.
Variant: The patient harbors the NM_001034853.2(RPGR):c.3457T>A (p.Ter1153Lys) variant in the hemizygous state.
ClinVar: 931960
gnomAD: This variant was not found in gnomAD v.2.1.1.
VariantEvidence: NM_001034853.2(RPGR):c.3457T>A (p.Ter1153Lys) is a stop-loss variant that triggers an extension of the C-terminus of RPGR by 38 amino acids. It is not predicted to undergo nonsense-mediated decay, and its inheritance pattern with largely unaffected female carriers is consistent with loss-of-function.
CaseAddInfo: The proband is a member of Family 1, with the mother being a female carrier with mild myopia, and an apparently affected maternal grandfather. Two other patients not known to be close relatives but harboring the same founder variant within a 29-megabase shared region received the same diagnosis of cone dystrophy.
CasePMIDs: N/A
IRD can be inherited as autosomal recessive (AR)
Case#: Jespersgaard_2019_Patient_165, gender and age not specified, origin likely to be Danish based on cohort
CasePresentingHPOs: N/A
CaseHPOFreeText: The proband has been diagnosed with retinitis pigmentosa, as part of a larger group of generalized non-syndromic retinal dystrophies. Detailed phenotypes are not described.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Next-generation sequencing was performed focusing on a targeted panel of 125 genes known to be linked to inherited retinal disease.
CaseMethod1: NGS panel
CaseMethod2: N/A
CaseGenotypingMethod: Next-generation sequencing was performed focusing on a targeted panel of 125 genes known to be linked to inherited retinal disease. It is not clear whether Sanger sequencing was used to validate the genotyping of this particular case.
Variant: The proband harbors the NM_000440.3(PDE6A):c.1620+1G>A variant in the homozygous state.
ClinVar: 636054
gnomAD: The NM_000440.3(PDE6A):c.1620+1G>A variant is found in gnomAD v2.1.1 at a frequency of 0.00003267 (1/30608) in the South Asian population https://gnomad.broadinstitute.org/variant/5-149275918-C-T
VariantEvidence: The NM_000440.3(PDE6A):c.1620+1G>A variant disrupts a canonical splice site in intron 12, but does not have experimental confirmation of exon skipping or frameshift.
CaseAddInfo: N/A
CasePMIDs: N/A
Herein, we report the identification of a novel nonsense mutation in the second exon of the KCNJ13 gene that leads to a premature stop codon in association with LCA16. We have determined that the mutation results in a severe truncation of the Kir7.1 C-terminus, alters protein localization, and disrupts potassium currents. Coexpression of the mutant and wild-type channel has no negative influence on the wild-type channel function, consistent with the normal clinical phenotype of carrier individuals.
Case#: Pattnaik_2015_Proband, male, age 10 years, family national origin described as Jordanian
CasePresentingHPOs: Nyctalopia HP:0000662, Childhood onset HP:0011463, Severely reduced visual acuity HP:0001141, Granular macular appearance HP:0007793, Retinal arteriolar constriction HP:0008043, Retinal degeneration HP:0000546, Abnormal choroid morphology (hypertrophy) HP:0000610
CaseHPOFreeText: The proband has been diagnosed at different times with Stargardt disease, retinitis pigmentosa, cone-rod dystrophy, and Leber congenital amaurosis, first presenting with night vision difficulties at age 2 years. Small focal sub-RPE deposits were observed.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: The proband was initially genotyped by PCR-based screening for known LCA-associated variants and next-generation sequencing focused on a 19-gene LCA panel.
CaseMethod1: PCR-based screening for known LCA-associated variants as well as next-generation sequencing of a 19-gene LCA panel
CaseMethod2: Sanger sequencing of gaps and low-coverage regions as well as for confirmation of the variants detected by other methods.
CaseGenotypingMethod: The proband was initially genotyped by PCR-based screening for known LCA-associated variants and next-generation sequencing focused on a 19-gene LCA panel. Sanger sequencing of gaps and low-coverage regions as well as for confirmation of the variants detected by other methods.
Variant: The individual is homozygous for the NM_002242.4(KCNJ13):c.158G>A (p.Trp53Ter) variant.
ClinVar: 224857
gnomAD: The variant is not found in gnomAD version 4.1.0.
VariantEvidence: Heterologous expression of the NM_002242.4(KCNJ13):c.158G>A (p.Trp53Ter) variant in CHO-K1 cells revealed that the variant channel retained very little ability to enable the flow of current, with the measurement of -68.8pA more comparable to the negative control (-42.4pA) than to the wild-type control (-588.7pA).
CaseAddInfo: The family history does not reportedly indicate consanguinity.
CasePMIDs: N/A
We have identified two Asian families with two novel homozygous mutations in the CLN5 gene.
GroupName: Lebrun_2009_Group_1
GroupPresentingHPOs: HP:0001251 (Ataxia), HP:0001250 (Seizure), HP:0002463 (Language impairment), HP:0011463 (Childhood onset)
GroupNotHPOs: N/A
NumberMales: 3
NumberFemales: 1
CountryOrigin: One family is from the United Kingdom, while the other family's country of origin is not mentioned
Ethnicity: One family is of Pakistani ethnic origin, while the second family is of Afghan ethnic origin
Race: Not clearly described, but both families have origins within a similar region of Asia.
AgeRange: Onset occurred between the ages of 2 and 5
TotalNumber: 4
FamilyInfo: 4
NoFamily: 0
VariantCount: 4
NonVariant: 0
OtherVariant: 0
GroupPreviousTesting: Genome-wide methods were not initially used, as clinical phenotypes were consistent with diagnosis of neuronal ceroid lipofuscinosis (NCL). Enzymatic tests ruled out defects in the CLN1, CLN2, and CLN10 loci, while CLN3, CLN6, and CLN8 defects were ruled out by Sanger sequencing of the coding regions. SNP array-based homozygosity mapping was performed, revealing 7 homozygous candidate regions in the affected members from the (consanguineous) family. These regions were analyzed for candidate NCL genes, finding CLN5 as the most likely locus to harbor the causative variant.
GroupMethod1: SNP array-based homozygosity mapping was performed, revealing 7 homozygous candidate regions in the affected members from the (consanguineous) family. These regions were analyzed for candidate NCL genes, finding CLN5 as the most likely candidate for further genotyping.
GroupMethod2: N/A
GroupGenotypingMethod: CLN5 mRNA was reverse transcribed, PCR-amplified, and subjected to Sanger sequencing.
GroupAddInfo: N/A
first reported CLN5 patients
Case#: Lebrun_2009_Patient_2, male, age 2-3 at onset, age 15 at death, family ethnicity reported as Afghan
CasePresentingHPOs: HP:0001251 (Ataxia), HP:0002474 (Expressive language delay), HP:0001250 (Seizure), HP:0011463 (Childhood onset), HP:0011421 (Death in adolescence)
CaseHPOFreeText: Onset was at age 2-3, with the first presenting phenotypes being ataxia and delay in speech development. Seizures began at age 4. Death occurred at age 15.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: The extent of previous testing within this patient is unclear.
CaseMethod1: N/A
CaseMethod2: N/A
CaseGenotypingMethod: CLN5 mRNA was reverse transcribed, PCR-amplified, and subjected to Sanger sequencing. This process was performed for both affected and control individuals (parents).
Variant: The patient is homozygous for the NM_006493.4(CLN5):c.990G>T (p.Trp330Cys) variant, (although this variant is referred to in the article as c.1137G>T (p.Trp379Cys)).
ClinVar: 56530
gnomAD: The variant is reported to have a maximum allele frequency of 0.00006484 (in the European non-Finnish population, with no homozygous individuals). https://gnomad.broadinstitute.org/variant/13-77575017-G-T
VariantEvidence: The missense variant introduces an additional cysteine into the protein product, potentially disrupting folding and three-dimensional structure. Immunofluorescent detection of the exogenously expressed variant in COS7 cells shows aberrant localization to the ER in contrast to the wild-type localization to the lysosome (Figure 3).
CaseAddInfo: The patient's family is consanguineous, as parents are described as first degree cousins. Parents were heterozygous for the variant. Family relationships between individuals were verified.
CasePMIDs: N/A
No evidence for a founder allele was found for the families carrying the stop mutation C35X (Fig. 2b).
Case#: Pusch_2000_Familly_9606_Proband, male, age and race not mentioned
CasePresentingHPOs: HP:0030640 (Complete congenital stationary night blindness), HP:0007663 (Reduced visual acuity), HP:0031624 (Moderate myopia), HP:0007984 (Electronegative electroretinogram)
CaseHPOFreeText: ERG with absent oscillatory-potential wavelets
CaseNotHPOs: HP:0001098 (Abnormal fundus morphology), HP:0030473 (Abnormal light-adapted flicker electroretinogram)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
CaseMethod1: Sanger sequencing of PCR amplified exons from NYX
CaseMethod2: N/A
CaseGenotypingMethod: The proband and family members were subjected to Sanger sequencing of NYX to identify the variant.
Variant: The proband harbors the NM_001378477.3(NYX):c.90C>A (p.Cys30Ter) variant on the X chromosome.
ClinVar: 11422
gnomAD: NM_001378477.3(NYX):c.90C>A (p.Cys30Ter) was not found in gnomAD.
VariantEvidence: This nonsense variant is located in exon 2/3 and is predicted to trigger NMD. It introduces a premature stop codon that would truncate 93% of the protein product.
CaseAddInfo: This variant appears not only in Family 9606, but also in Family 2438T, yet is not suspected to be a founder alelle.
CasePMIDs: N/A
PDE6C hydrolyzed cGMP with a Km of 65 ± 6 μm and kcat of 4400 ± 300 s−1 (Fig. 7A).
Selection B- Gene function is consistent with phenotype.
GOterm: GO:0047555 (3',5'-cyclic-GMP phosphodiesterase activity)
FunctionalEvidence: Purified PDE6C hydrolyzed cGMP with a Km and kcat slightly lower than trypsin-activated bovine rod PDE6 (Figure 7A).
FunctionalHPO: HP:0000551 (Color vision defect), HP:0030465 (Undetectable light-adapted electroretinogram)
Characterization of Human Cone Phosphodiesterase-6 Ectopically Expressed in Xenopus laevis Rods
PMID: 19801642
Gene: PDE6C
HGNC: 8787
Disease: cone dystrophy 4
MONDO: 0013129
InheritancePattern: recessive
Prevalence: cone dystrophy in general is estimated to have a prevalence of 1 in 40,000 (PMID: 30578485).
Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.
An 18-year old highly myopic woman presented with bilateral retinoschisis associated with a unilateral macular hole in the right eye and vitreomacular traction in the left eye. Methods: Genetic studies disclosed a heterozygous pathogenic variant in the KCNJ13 gene was identified (c.484C>T (p.Arg162Trp)), consistent with a diagnosis of snowflake vitreoretinal degeneration (SVD). Results: While there were no corneal guttata, juvenile cataracts, or perivascular sheathing in this case, salient features of SVD included a fibrillar vitreous structure, crystalline retinopathy, and flattened optic nerves. The patient developed a FTMH in the left eye at 17 months follow up, followed by a rhegmatogenous retinal detachment (RRD) requiring 2 surgical repairs.
Case#: Ashkenazy_2023_Proband, female, age 18 at time of report, family origin unknown due to adoption but reported in the United States
CasePresentingHPOs: Snowflake vitreoretinal degeneration HP:0011533, High myopia HP:0011003, Retinoschisis HP:0030502, Rhegmatogenous retinal detachment HP:0012230, Abnormal vitreous humor morphology HP:0004327, Full-thickness macular hole HP:0031152
CaseHPOFreeText: The patient exhibited fibrillar vitreous structure, crystalline retinopathy, and optic nerve flattening.
CaseNotHPOs: Corneal guttata HP:0012038, Presenile cataracts HP:0007819
CaseNotHPOFreeText: Perivascular sheathing was absent.
CasePreviousTesting: Genotyping of the proband was not described in detail, but reportedly did not include whole exome sequencing, due to the specificity of the phenotype. Genes implied to have been possibly examined were COL2A1, COL11A1, and CSPG2.
CaseMethod1: Sanger sequencing of KCNJ13
CaseMethod2: N/A
CaseGenotypingMethod: Genotyping of the proband was not described in detail, but reportedly did not include whole exome sequencing, due to the specificity of the phenotype. Genes implied to have been possibly examined were COL2A1, COL11A1, and CSPG2. Sanger sequencing of KCNJ13 was performed.
Variant: The individual harbors the NM_002242.4(KCNJ13):c.484C>T (p.Arg162Trp) variant in the heterozygous state.
ClinVar: 6585
gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.0000008536 (1 / 1,171,470) in the European (non-Finnish) population https://gnomad.broadinstitute.org/variant/chr2-232768790-G-A?dataset=gnomad_r4
VariantEvidence:NM_002242.4(KCNJ13):c.484C>T (p.Arg162Trp) is a missense variant that has functional evidence of electrophysiological abnormalities and loss of sensitivity to different K+ concentrations, when exogenously expressed in CHO cells (PMID: 18179896, Figure 2).
CaseAddInfo: The proband may or may not be a relative of the family previously reported with the same variant in PMID: 18179896, as both appear to have received medical care in the United States.
CasePMIDs: N/A
Further, over expression of hPrp4(Pro315Leu), but not hPrp4(WT), triggered systemic deformities in wild-type zebrafish embryos with the retina primarily affected, and dramatically augmented death rates in morphant embryos, in which orthologous zebrafish prpf4 gene was silenced. We conclude that mutations of PRPF4 cause RP via haploinsufficiency and dominant-negative effects, and establish PRPF4 as a new U4/U6-U5 snRNP component associated with adRP.
ExperimentName: "Variant overexpression in zebrafish causes defects in visual function."
NonHumanModel: Danio rerio
GeneAlteration: The model animals have been subjected to microinjection of PRPF4 mRNA (either wild-type or harboring the p.Pro315Leu variant), with expression levels comparable to the endogenous gene.
ModelPhenotype: Photoreceptor layer loss on macular OCT HP:0030609, Inner retinal layer loss on macular OCT HP:0030620, Photoreceptor outer segment loss on macular OCT HP:0030610
HumanPhenotype: Constriction of peripheral visual field HP:0001133, Reduced visual acuity HP:0007663,, Decreased light- and dark-adapted electroretinogram amplitude HP:0000654. Retinal degeneration HP:0000546, Macular degeneration HP:0000608, Optic disc pallor HP:0000543, Attenuation of retinal blood vessels HP:0007843, Pigmentary retinopathy HP:0000580
ModelEvidence: The variant causes severely disrupted photoreceptors in the retina (Figure 5D), reduced rhodopsin staining (rod marker) in the IS/OS layer (Figures 5E-5J) and other deformities such as malformed brains, short trunks, cardiac edema and curved body axis, at higher levels than in the wild-type control (Figures 5B and 5C). The retinal transcripts opn1lw1, gnat2, rs1, snrpg, prph2b, gnb3, and rho were decreased in the variant-expressing zebrafish (Figure 5K), while the splicing factor transcripts prpf4, prpf3, prpf31, prpf6, prpf8, snrnp200, eftud2, and sart1 were increased (Figures 5A, 5L).
ModelVariant: This model introduced the disease-associated variant NM_001244926.2(PRPF4):c.941C>T (p.Pro314Leu) in the heterozygous state (ClinVar ID: 143057).
The ophthalmic phenotype of IFT140-related ciliopathy ranges from isolated to syndromic congenital retinal dystrophy
PMID: 26359340
Gene: IFT140
HGNC: 29077
Disease: Retinitis pigmentosa 80
MONDO: 0054708
InheritancePattern: autosomal recessive
Prevalence: The overall prevalence of Retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of Retinitis pigmentosa with a recessive mode of inheritance is estimated to be 65-85% (between 1 in 3,500 and 1 in 6,500).
Penetrance: Disease caused by biallelic IFT140 variants appears to be fully penetrant.
Localization of the Functional Domains of Human Tissue Inhibitor of Metalloproteinases-3 and the Effects of a Sorsby's Fundus Dystrophy Mutation
PMID: 9642234
Gene: TIMP3
HGNC: 11822
Disease: Sorsby fundus dystrophy (SFD), also known as Sorsby's fundus dystrophy, Sorsby pseudoinflammatory fundus dystrophy, or hemorrhagic macular dystrophy
MONDO: 0007640
InheritancePattern: Autosomal Dominant
Prevalence: Estimated at 1 in 220,000 (PMID: 28847738)
Penetrance: Fully penetrant, onset between the third and sixth decades of life
Mutations in IMPG2, Encoding Interphotoreceptor Matrix Proteoglycan 2, Cause Autosomal-Recessive Retinitis Pigmentosa
PMID: 20673862
Gene: IMPG2
HGNC: 18362
Disease: retinitis pigmentosa 56
MONDO: 0013314
InheritancePattern: semi-dominant
Prevalence: Vitelliform macular dystrophy in general is estimated to have a prevalence of 1 in 5,500 (PMID: 27120116).
Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete, while heterozygous carriers of deleterious variants show incomplete penetrance and variable expressivity.
MOL0732
Case#: Bandah-Rozenfeld_2010_MOL0732_proband, female, age 63 years at time of diagnosis, ethnic origin reported as Israeli Christian Arab
CasePresentingHPOs: HP:0008002 (Abnormality of macular pigmentation), HP:0030613 (Abnormal foveal morphology on macular OCT), HP:0030557 (Best corrected visual acuity 0.4 LogMAR), HP:0000603 (Central scotoma), HP:0031729 (Moderate hypermetropia), HP:0000518 (Cataract)
CaseHPOFreeText: The patient has been diagnosed with mild maculopathy. "Abnormal foveal morphology" refers to elevation of the photoreceptor layer in foveal region by OCT analysis. The "cataract" specifically refers to mild nuclear sclerosis.
CaseNotHPOs: HP:0000512 (Abnormal electroretinogram), HP:0000551 (Color vision defect)
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous genotyping consisted of autozygosity mapping.
CaseMethod1: Homozygosity mapping
CaseMethod2: Sanger sequencing of the 19 exons of the IMPG2 gene
CaseGenotypingMethod: Genotyping consisted of autozygosity mapping followed by Sanger sequencing of the 19 exons of the IMPG2 gene.
Variant: The patient harbors the NM_016247.4(IMPG2):c.370T>C (p.Phe124Leu) variant in the homozygous state.
ClinVar: 3550
gnomAD: The NM_016247.4(IMPG2):c.370T>C (p.Phe124Leu) variant is found in gnomAD v2.1.1 at a maximum allele frequency of 0.0001318 (17/129010, with 0 homozygotes) in the European (non-Finnish) population. https://gnomad.broadinstitute.org/variant/3-101023121-A-G
VariantEvidence: NM_016247.4(IMPG2):c.370T>C (p.Phe124Leu) is a missense variant in exon 3 of 19 that does not have evidence of impact on the protein product.
CaseAddInfo: The family is consanguineous, with the parents being first cousins.
CasePMIDs: A publication by a separate group referred to this case as autosomal recessive vitelliform macular dystrophy, but did not indicate the existence of any additional details about the case (PMID: 25085631).
Whole exome sequencing revealed novel pathogenic variants in Vietnamese patients with FEVR
PMID: 37089697
Gene: CTNNB1
HGNC: 2514
Disease: severe intellectual disability-progressive spastic diplegia syndrome
MONDO: 0014035
InheritancePattern: autosomal dominant
Prevalence: The incidence is unknown but estimated to be between 1 in 30,000 and 1 in 40,000 births (PMID: 32168371).
Penetrance: The penetrance of the cognitive impairment phenotype among cases appears to be near-complete, while the exudative vitreoretinopathy phenotype reportedly has a prevalence of ~39% among affected individuals with a syndromic diagnosis.
Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa
PMID: 9501220
Gene: RPE65
HGNC: 10294
Disease: Retinitis pigmentosa 20
MONDO: 0013425
InheritancePattern: Autosomal Recessive
Prevalence: The overall prevalence of Retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of recessive Retinitis pigmentosa caused by RPE65 variants is ~2%. (PMID: 9501220) Thus, the prevalence of Retinitis pigmentosa 20 is between 1 in 150,000 and 1 in 200,000.
Penetrance: Fully penetrant, with onset typically in childhood
Retinal degeneration slow (rds) is a retinal disorder of an inbred strain of mice in which the outer segment of the photoreceptor cell fails to develop.
ExperimentName: The rds mouse harbors loss-of-function variants in the Prph2 gene.
NonHumanModel: Mus musculus
GeneAlteration: The model animals are homozygous for a loss-of-function variant in the Prph2 locus known as retinal degeneration slow (rds). The causal variant appears to encode a p.Gln340Pro missense change that results in the inability to detect the Prph2 protein by antibody.
ModelPhenotype: HP:0000546 (Retinal degeneration), HP:0030610 (Photoreceptor outer segment loss on macular OCT)
HumanPhenotype: HP:0030643 (Vitelliform-like retinal lesions), HP:0000533 (Chorioretinal atrophy), HP:0001105 (Retinal atrophy), HP:0007663 (Reduced visual acuity), HP:0000580 (Pigmentary retinopathy), HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0008275 (Abnormal light-adapted electroretinogram), HP:0007843 (Attenuation of retinal blood vessels), HP:0011506 (Choroidal neovascularization), HP:0030499 (Macular drusen)
ModelEvidence: This is a naturally occurring mouse model with homozygous disruption of the Prph2 locus. Phenotypes include progressive degeneration of retina, absence of rods at age 7-10 months, and reduction of the number of rows of photosensitive cell nuclei to only 1-4 rows (described in previous publications PMID: 705766 and PMID: 419532). Other previous publications have reported that the mice exhibit abnormal development of photoreceptor outer segments, as well as subsequent gradual photoreceptor degeneration of photoreceptors that is complete by age 1 year (PMID: 2918924).
ModelVariant: This model did not introduce a disease-associated variant known from an affected human patient, but rather studied a naturally occurring p.Gln340Pro missense variant disrupting the Prph2 locus.
Molecular genetic and clinical evaluation of three Chinese families with X-linked ocular albinism
PMID: 28211458
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
Autosomal Recessive Familial Exudative Vitreoretinopathy Is Associated with Mutations in LRP5
PMID: 15346351
Gene: LRP5
HGNC: 6697
Disease: osteoporosis-pseudoglioma syndrome
MONDO: 0009820
InheritancePattern: autosomal recessive
Prevalence: osteoporosis-pseudoglioma syndrome is estimated to occur in 1 out of every 2,000,000 live births.
Penetrance: The penetrance of the phenotype among homozygous or compound heterozygous cases appears to be complete, while heterozygous carriers of deleterious variants appear to be mildly affected.
R838C
Case#: Kelsell_1998_CORD6_Family_2_Proband, female, age 45 at time of report, nationality listed as British
CasePresentingHPOs: HP:0007401 (Macular atrophy), HP:0000548 (Cone/cone-rod dystrophy)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
CaseMethod1: Sanger sequencing of PCR products from each of the 18 exons of the GUCY2D locus
CaseMethod2: HhaI restriction digest of the PCR-amplified exon 13
CaseGenotypingMethod: The proband and her family members were subjected to sequencing of PCR products from each of the 18 exons of the GUCY2D locus. The PCR-amplified product from exon 13 was then subjected to HhaI restriction digest and resolved by agarose gel electrophoresis.
Variant: The proband harbors the NM_000180.4(GUCY2D):c.2512C>T (p.Arg838Cys) variant in the heterozygous state.
ClinVar: 9355
gnomAD: The variant is present in gnomAD at a frequency of 0.000007744 (1/129124) in the European non-Finnish population, with no homozygotes. https://gnomad.broadinstitute.org/variant/17-7918018-C-T
VariantEvidence: NM_000180.4(GUCY2D):c.2512C>T (p.Arg838Cys) is a missense variant located within the coiled-coil domain that mediates GUCY2D dimerization. Codon 838 has proven to be a hot spot disrupted in other families similarly affected with autosomal dominant cone-rod dystrophy (PMID: 11115851, PMID: 12552567, PMID: 26298565). The p.Arg838Cys substitution has been shown to disrupt the calcium sensitivity of GUCY2D and to trigger the inability to inactivate cyclase activity at high physiological calcium ion concentrations (PMID: 11115851).
CaseAddInfo: N/A
CasePMIDs: N/A
The RPE and photoreceptors in Timp3 mutant mice degenerated at low doses of sodium iodate, which had no effect in wildtype control mice. These studies suggest that TIMP3 mutations may result in a dysregulation of pro-oxidant—antioxidant homeostasis in the RPE, leading to RPE degeneration in SFD.
ExperimentName: Oxidative stress sensitivity in the homozygous Timp3Ser179Cys Knock-In Mouse
NonHumanModel: Mus musculus (C57Bl/6J background)
GeneAlteration: The gene alteration was constructed in a previous paper (PMID:12147610), in which the mouse Timp3 ortholog was subjected to site-directed mutagenesis to introduce a change equivalent to the human variant encoding the Ser179Cys substitution associated with Sorsby Fundus Dystrophy (PMID:8634721). This variant was introduced into embryonic stem cells by homologous recombination, generating animals for germline transmission of the Timp3Ser179Cys knock-in allele of interest.
ModelPhenotype: HP:0000580 (Pigmentary retinopathy), HP:0007703 (Abnormality of retinal pigmentation)
HumanPhenotype: HP:0007703 (Abnormality of retinal pigmentation)
ModelEvidence: The phenotypes of this model system recapitulate some of the degenerative features of the human model. Sensitivity to oxidative stress was revealed when low-dose sodium iodate triggered RPE degeneration and disorganization in the Timp3 S179C/S179C mice but not the wild-type controls (Figure 4). Rhodamine-phalloidin staining also exhibited an increased area of degeneration in the central region of the RPE in mutant mice but not in the wild-type controls (Figure 5). It is important to point out the caveat that the mice were homozygous for Timp3 Ser179Cys, whereas human patients are heterozygous. This difference in genotype introduces the possibility of loss-of-function effects that are specific to the mouse but absent from the human patients.
ModelVariant: The model variant is a knock-in modification to the mouse Timp3 ortholog that is equivalent to the human NM_000362.5(TIMP3):c.536C>G, (p.Ser179Cys) missense variant (ClinVar:12678).
II.1
Case: Gliem_2000_Family_1_patient_II.1, female, country of origin Germany, onset at 47 years of age
DiseaseAssertion: Sorsby's fundus dystrophy
FamilyInfo: The variant was inherited by the proband rather than acquired de novo.
CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0007663 (Reduced visual acuity), HP:0011510 (Drusen), HP:0000533 (Chorioretinal atrophy)
CaseHPOFreeText: Presentation at age 47 with nyctalopia. Evaluation at age 61 showed drusen deposits in macular area, near optic disk and along vascular arcades, central and midperipheral atrophy, and reduced choroidal thickness.
CaseNOTHPOs: HP:0011506 (Choroidal neovascularization)
CaseNOTHPOFreeText: N/A
CasePreviousTesting: Phenotypic characterization only
GenotypingMethod: Sanger sequencing of PCR products from all 5 exons and flanking splice junctions of the TIMP3 gene.
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: Proband harbors the NM_000362.5(TIMP3):c.530A>G (p.Tyr177Cys) missense variant.
CAID: CA411540328
gnomAD: Variant is absent from gnomAD.
VariantEvidence: This missense variant within exon 5 of TIMP3 results in an unpaired Cys residue.
Twenty-one probands of three unrelated families with SFD were investigated using wide-field imaging, confocal laser scanning ophthalmoscopy with autofluorescence imaging, optical coherence tomography (OCT), indocyanine green–angiography (ICG-A), and molecular diagnostic for causative mutations.
Group Phenotypes
GroupName: Gliem_2015_Group_1
GroupPresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0000533 (Chorioretinal atrophy), HP:0000662 (Nyctalopia)
GroupHPOFreeText: Central and midperipheral atrophy, Central fibrosis, Dark adaptation problems, Progressive loss of visual acuity
GroupNotHPOs: N/A
GroupDemographics
NumberMales: 7
NumberFemales: 13
CountryOrigin: Germany
Ethnicity: Not mentioned
Race: Not mentioned
AgeRange: 52-79 at time of evaluation
TotalNumber: 20
GroupPreviousTesting: N/A
GroupGenotypingMethod Sanger sequencing of PCR products from all 5 exons and flanking splice junctions of the TIMP3 gene.
GroupAddInfo: The group consisted of 3 unrelated families.
Sorsby Fundus Dystrophy: Novel Mutations, Novel Phenotypic Characteristics, and Treatment Outcomes
PMID: 25766588
Gene: TIMP3
HGNC: 11822
Disease: Sorsby fundus dystrophy (SFD), also known as Sorsby's fundus dystrophy, Sorsby pseudoinflammatory fundus dystrophy, or hemorrhagic macular dystrophy
MONDO: 0007640
InheritancePattern: Autosomal Dominant
Prevalence: Estimated at 1 in 220,000 (PMID: 28847738)
Penetrance: Fully penetrant, onset between the third and sixth decades of life
Evidence for a Retroviral Insertion in TRPM1 as the Cause of Congenital Stationary Night Blindness and Leopard Complex Spotting in the Horse
PMID: 24167615
Gene: TRPM1
HGNC: 7146
Disease: congenital stationary night blindness 1C
MONDO: MONDO:0013183
InheritancePattern: autosomal recessive
Prevalence: Congenital stationary night blindness has an estimated prevalence between 1 in 6,000 (PMID: 31427709) and 1 in 300,000 (PMID: 3487908). However, the prevalence of congenital stationary night blindness 1C specifically is unknown.
Penetrance: Penetrance is thought to be complete.
Previous gene expression analyses [17] did not detect expression of TRPM1 in the skin and retina of LP/LP CSNB individuals, suggesting that transcription of this gene was disrupted. However, when comparing raw read counts, we identified novel expression within intron 1, having 85 reads in the skin and 460 reads in the retina of the LP/LP horse compared to 0 and 4 reads (in the skin and retina respectively) of the lp/lp horse (Figure 3). De novo assembly of this transcript followed by PCR and genomic DNA sequencing identified a 1378 bp insertion in intron 1 (ECA1g. 108,297,929_108,297,930 ins1378) of TRPM1. In order to characterize this insertion we performed a blast analysis using RepeatMasker [27] (Figure S2). This insertion is a long terminal repeat (LTR) of an endogenous retrovirus (ERV) class II retro-element and is characterized by flanking regions of micro-homology, indicative of non-homologous end joining double stranded break repair as the mechanism of insertion (Figure 4A and Figure S2). Detection of this insertion by allele specific PCR confirmed complete association with the LP genotype (as predicted by phenotype) in tests of 511 horses (χ2=1022.00, p<<0.0005) and CSNB status in tests of 43 horses (χ2=43, p<<0.0005) (Table 2).
ExperimentName: Horse model of TRPM1 loss-of-function
NonHumanModel: Equus ferus caballus
GeneAlteration: The horse has homozygous disruption of the TRPM1 gene by a naturally occurring insertion of a 1378 bp transposon in intron 1 (g. 108,297,929_108,297,930 ins1378). A previous publication by the same group has shown that TRPM1 expression is absent from the skin and retina of these horses (PMID: 18660533).
ModelPhenotype: HP:0001053 (Hypopigmented skin patches), HP:0000591 (Abnormal sclera morphology), HP:0000662 (Nyctalopia), HP:0007984 (Electronegative electroretinogram),
HumanPhenotype: HP:0000662 (Nyctalopia), HP:0000545 (Myopia), HP:0000572 (Visual loss), HP:0007984 (Electronegative electroretinogram), HP:0000958 (Dry skin), HP:0000964 (Eczema)
ModelEvidence: The affected horses exhibit night blindness and abnormal dark-adapted ERG with absent b-wave and increased amplitude of a-wave (Figure 1). Both phenotypes are similar to the affected human patients. Melanocyte dysfunction is also shown by unpigmented areas of the skin (Figures 1 and 2) and the sclera of the eye (Figure 2A). These pigment phenotypes do not have a human equivalent, although some affected patients have been reported to have dry skin or a history of eczema (PMID: 19878917).
ModelVariant: The model harbors a naturally occurring variant that does not have an equivalent / orthologous variant reported in human patients.
Mutations in the Cone Photoreceptor G-Protein α-Subunit Gene GNAT2 in Patients with Achromatopsia
PMID: 12077706
GeneName: GNAT2
HGNC: 4394
Disease: achromatopsia 4
MonDO ID: MONDO_0013465
Inheritance: autosomal recessive
RPGR is mutated in patients with a complex X linked phenotype combining primary ciliary dyskinesia and retinitis pigmentosa
PMID: 16055928
Gene: RPGR
HGNC: 10295
Disease: RPGR-related retinopathy
MONDO: MONDO:0100437
InheritancePattern: X-linked
Prevalence: The prevalence of RPGR-related retinopathy is calculated to be approximately 1 in 214,000, based on the known incidence of retinitis pigmentosa at 1 in 3,000, the proportion of retinitis pigmentposa that is X-linked at 20%, and the proportion of X-linked retinitis pigmentosa that is RPGR-associated at 70% (PMID: 34985506).
Penetrance: Penetrance is nearly 100% in hemizygous males but is incomplete and dependent upon the variant in heterozygous female carriers.
The Y141C knockin mutation in RDS leads to complex phenotypes in the mouse
PMID: 25001182
Gene: PRPH2
HGNC: 9942
Disease: retinitis pigmentosa 7
MONDO: 0011974
InheritancePattern: semi-dominant
Prevalence: The incidence of PRPH2-related cases among inherited retinal dystrophies is reported to range from 3.5% in North America to 10.3% in France (PMID: 36010202).
Penetrance: The penetrance among biallelic cases appears to be complete, while the monoallelic cases exhibit incomplete penetrance (PMID: 36609934).
we generated a knockin mouse model expressing an RDS pattern dystrophy mutation, Y141C. Y141C mice exhibited clinical signs similar to those in patients including late-onset fundus abnormalities characteristic of RPE and choroidal defects and electroretinogram defects. Ultrastructural examination indicated that disc formation was initiated by the Y141C protein, but proper sizing and alignment of discs required wild-type RDS. The biochemical mechanism underlying these abnormalities was tied to defects in the normal process of RDS oligomerization which is required for proper RDS function. Y141C-RDS formed strikingly abnormal disulfide-linked complexes which were localized to the outer segment (OS) where they impaired the formation of proper OS structure.
ExperimentName: Knockin of the p.Tyr141Cys variant into mouse Prph2 results in retinal defects.
NonHumanModel: Mus musculus
GeneAlteration: The model animals are heterozygous for knock-in of the p.Tyr141Cys variant into the Prph2 locus.
ModelPhenotype: HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0000546 (Retinal degeneration), HP:0030610 (Photoreceptor outer segment loss on macular OCT), HP:0012045 (Retinal flecks)
HumanPhenotype: HP:0030643 (Vitelliform-like retinal lesions), HP:0000533 (Chorioretinal atrophy), HP:0001105 (Retinal atrophy), HP:0007663 (Reduced visual acuity), HP:0000580 (Pigmentary retinopathy), HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0008275 (Abnormal light-adapted electroretinogram), HP:0007843 (Attenuation of retinal blood vessels), HP:0011506 (Choroidal neovascularization), HP:0030499 (Macular drusen)
ModelEvidence: This knock-in mouse model has normal expression and localization of Prph2 (Fig. 1), but exhibits phenotypes including photoreceptor outer segment loss (Fig. 2), decreased rod ERG (Fig. 3A), and photoreceptor layer degeneration (Fig. 4). Homozygous mice showed decreased cone ERG as well (Figs. 3B, 3C). Yellow retinal flecks were observed in the fundus (Fig. 5). Abnormal high molecular weight complexes containing Prph2 were also observed in western blotting, along with the absence of normal monomers and dimers in the homozygous animals (Figs. 6 and 7).
ModelVariant: This mouse model has introduced a disease-associated variant known from an affected human patient, NM_000322.5(PRPH2):c.422A>G (p.Tyr141Cys), ClinVar ID: 98666.
We demonstrated that TIMP3 deficiency in the mouse causes a distinct choroidal, but not retinal, phenotype characterized by prominently enlarged choroidal blood vessels. Thus, this study provides the first in vivo evidence in support of the hypothesized role of TIMP3 in the regulation of choroidal vascularization of the retina.
ExperimentName: Phenotypic characterization of the homozygous Timp3-/- Knock-Out Mouse
NonHumanModel: Mus musculus (C57/Bl6 or CD1 background)
GeneAlteration: A neomycin resistance expression cassette was cloned into plasmid-borne exon 3 of mouse Timp3. The linearized construct was transfected into embryonic stem cells and injected into blastocysts. Animals that had undergone homologous recombination were identified by locus-specific genomic PCR reactions. Predicted loss of Timp3 due to a premature stop codon and nonfunctional mRNA was confirmed at the protein level.
ModelPhenotype: HP:0030605 (Abnormal indocyanine green angiography), HP:0025568 (Abnormal morphology of the choroidal vasculature), HP:0030979 (Dilatation of large choroidal vessels)
HumanPhenotype: HP:0011506 (Choroidal neovascularization)
ModelEvidence: The model showed dilatation of the large choroid vessels, which appeared large and hyperfluorescent during ICG angiography, with balloon-like spots (Figure 3A-3B). While wild-type controls exhibited normal choroidal blood vessel network, Timp3-/- animals had abnormal vessel formations that were strongly dilated or fused (Figures 3C-3H). During in situ zymography, higher local fluorescence intensity indicated increased MMP2 and MMP9 activity in the knockout animals, as expected. Aortic explants from knockout mice showed higher spontaneous microvessel outgrowth than their counterparts from wild-type mice (Figure 6). Rescue assays suggest that the antiangiogenic activity requires the C-terminal region of TIMP3 (Figure 7).
ModelVariant: N/A (Timp3 knockout)
Generation of Bbs1M390R/M390R Knockin Mice. We targeted the Bbs1 gene in mice by constructing a vector containing regions of the mouse Bbs1 gene that replaced the normal methionine codon at position 390 in exon 12 with an arginine codon on homologous recombination (Fig. 1A). RT-PCR of cDNA amplified from the knockin mice confirmed that the M390R allele was spliced correctly without inclusion of the intronic neomycin cassette. Sequencing of the Bbs1M390R/M390R cDNA confirmed that the Bbs1 gene was modified with the incorporation of the homozygous methionine to arginine (ATG to AGG) change in the knockin line (Fig. 1B).
ExperimentName: Knock-in of the p.M390R variant into the mouse Bbs1 gene.
NonHumanModel: Mus musculus
GeneAlteration: The model animals have been subjected to homologous recombination-based knock-in of the p.M390R variant into exon 12 of the endogenous mouse Bbs1 gene. The variant has been studied in the homozygous state.
ModelPhenotype: HP:0032558 (Absent sperm flagella), HP:0010633 (Partial anosmia), HP:0012433 (Abnormal social behavior), HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0030610 (Photoreceptor outer segment loss on macular OCT), HP:0030609 (Photoreceptor layer loss on macular OCT), HP:0001513 (Obesity), HP:0002119 (Ventriculomegaly),
HumanPhenotype: HP:0000639 (Nystagmus), HP:0000510 (Rod-cone dystrophy), HP:0007663 (Reduced visual acuity), HP:0000662 (Nyctalopia), HP:0000518 (Cataract), HP:0008323 (Abnormal light- and dark-adapted electroretinogram), HP:0000107 (Renal cyst), HP:0001513 (Obesity), HP:0010442 (Polydactyly), HP:0002463 (Language impairment), HP:0000026 (Male hypogonadism)
ModelEvidence: Sperm flagella were absent (Figures 2A, 2B). Loss of the outer nuclear layer and degeneration of the photoreceptor inner and outer segments were observed in older mice (Figures 2C, 2D). Photoreceptor morphology in the outer segment was also disrupted in TEM images (Figure 2E). Scotopic responses showed a- and b-wave attenuation (Figure 2G), while photopic responses were not significantly different (Figure 2H). Homozygous mice showed obesity relative to wild-type and heterozygous mice (Figure 3). Brain sections showed neuroanatomical defects, especially ventriculomegaly (Figure 4). Brain cilia were morphologically abnormal (Figure 5). Renal cysts and polydactyly were investigated but not observed.
ModelVariant: This model introduced a disease-associated variant known from affected human patients (NM_024649.5(BBS1):c.1169T>G (p.Met390Arg), ClinVar ID: 12143).
OA1 mutations and deletions in X-linked ocular albinism.
PMID: 9529334
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
We also found reduced photoreceptor responses in Adam9 knockout mice, previously reported to be asymptomatic. In 12-month-old knockout mice, photoreceptors appear normal, but the apical processes of the retinal pigment epithelium (RPE) cells are disorganized and contact between photoreceptor outer segments (POSs) and the RPE apical surface is compromised. In 20-month-old mice, there is clear evidence of progressive retinal degeneration with disorganized POS and thinning of the outer nuclear layer (ONL) in addition to the anomaly at the POS-RPE junction. RPE basal deposits and macrophages were also apparent in older mice.
ExperimentName: Mouse model of Adam9 loss-of-function
NonHumanModel: Mus musculus
GeneAlteration: The mice harbor homozygous knockout of the Adam9 gene by an insertion of a neomycin selection cassette in to the exon encoding amino acids 32 to 66 of Adam9 (PMID: 11839819).
ModelPhenotype: HP:0000546 (Retinal degeneration), HP:0007703 (Abnormality of retinal pigmentation), HP:0030610 (Photoreceptor outer segment loss on macular OCT), HP:0030483 (Reduced amplitude of dark-adapted bright flash electroretinogram a-wave), HP:0007984 (Electronegative electroretinogram), HP:0008323 (Abnormal light- and dark-adapted electroretinogram)
HumanPhenotype: HP:0410280 (Pediatric onset), HP:0007663 (Reduced visual acuity), HP:0007401 (Macular atrophy), HP:0000580 (Pigmentary retinopathy), HP:0007769 (Peripheral retinal degeneration), HP:0008323 (Abnormal light- and dark-adapted electroretinogram), HP:0000548 (Cone/cone-rod dystrophy), HP:0007994 (Peripheral visual field loss), HP:0000545 (Myopia)
ModelEvidence: The affected mice exhibit an abnormal gap between the RPE and the photoreceptor outer segment, which would normally be in contact (Figure 5B). The gap contains macrophages (Figure 5L). Outer nuclear layer thinning is observed (Figure 5D), as well as material deposited between the RPE and Bruch's membrane, which may be analogous to drusen deposits in humans (Figure 5K). These findings collectively show an adhesion defect at the interface between the photoreceptor outer segment and the RPE. This evidence of retinal degeneration was complemented by abnormalities in both rod- and cone-driven ERG responses (Figure 4), matching a feature of the human patients.
ModelVariant: The model harbors a targeted disruption that does not have an equivalent / orthologous variant reported in human patients.
Direct sequencing of ADAM9 in MEP49 revealed a homozygous point mutation in exon 9, creating a premature stop codon (c.766C→T; p.R256X) (Figure 2A).
Case#: Parry_2009_Family_MEP49_patient_IV:5, male, age not specified, family origin reported to be Pakistani
CasePresentingHPOs: HP:0410280 (Pediatric onset), HP:0007663 (Reduced visual acuity), HP:0007401 (Macular atrophy), HP:0000580 (Pigmentary retinopathy), HP:0007769 (Peripheral retinal degeneration), HP:0008323 (Abnormal light- and dark-adapted electroretinogram)
CaseHPOFreeText: The proband was diagnosed with cone-rod dystrophy, with family showing autosomal recessive mode of inheritance. Most affected members of the proband's family had white patches around the optic disc and in the posterior pole.
CaseNotHPOs: HP:0000639 (Nystagmus), HP:0000613 (Photophobia)
CaseNotHPOFreeText: N/A
CasePreviousTesting: The proband and his family have been initially genotyped by autozygosity mapping with both 10k and 250k Affymetrix SNP arrays and microsatellite markers.
CaseMethod1: Autozygosity mapping
CaseMethod2: Sanger sequencing
CaseGenotypingMethod: The proband and his family have been initially genotyped by autozygosity mapping with both 10k and 250k Affymetrix SNP arrays and microsatellite markers. Sanger sequencing of the ADAM9 locus then identified the variants.
Variant: The proband harbors the NM_003816.3(ADAM9):c.766C>T (p.Arg256Ter) variant in the homozygous state.
ClinVar: 6877
gnomAD: This variant is found in gnomAD v2.1.1 at a frequency of 0.00003267 (1/30608) in the South Asian population, with no homozygotes. https://gnomad.broadinstitute.org/variant/8-38880696-C-T
VariantEvidence: NM_003816.3(ADAM9):c.766C>T (p.Arg256Ter) is a nonsense variant in exon 9 of 21, and is therefore predicted to result in nonsense-mediated decay.
CaseAddInfo: The proband's family is known to be consanguineous, with the parents being first cousins (pedigree shown in Figure 2).
CasePMIDs: N/A
patients
Case#: Olivier_2021_Family_K_Proband_II:3, male, age 43 years at the time of onset, national origin reported as Spanish
CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0001099 (Fundus atrophy), HP:0007737 (Bone spicule pigmentation of the retina)
CaseHPOFreeText: The proband has onset of retinitis pigmentosa at the age of 43 years.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: It is not clear whether previous testing methods included systematic genotyping of loci associated with VMD or RP.
CaseMethod1: Screening of IMPG1 using either gene panel testing or exome sequencing
CaseMethod2: Sanger sequencing-based confirmation
CaseGenotypingMethod: Genotyping is not entirely clear but has at least included panel-based analysis of the IMPG1 locus and Sanger sequencing-based confirmation.
Variant: The proband harbors the NM_001563.4(IMPG1):c.1982G>A (p.Arg661His) variant in the homozygous state.
ClinVar ID: 1056230
gnomAD: The NM_001563.4(IMPG1):c.1982G>A (p.Arg661His) variant is found in gnomAD v2.1.1 at a frequency of 0.00004006 (1/24964) in the African / African-American population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/6-76657093-C-T
VariantEvidence: NM_001563.4(IMPG1):c.1982G>A (p.Arg661His) is a missense variant, which does not have experimental evidence of a functional effect on the protein product.
CaseAddInfo: The patient's affected sister shares the same homozygous genotype.
CasePMIDs: N/A
RP
Case#: Olivier_2021_Family_H_Proband_II:1, male, age 53 years at the time of diagnosis, national origin reported as French
CasePresentingHPOs: HP:0007401 (Macular atrophy), HP:0007737 (Bone spicule pigmentation of the retina)
CaseHPOFreeText: The proband has been diagnosed with maculopathy at the age of 53 years, and exhibits retinal discoloration.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: It is not clear whether previous testing methods included systematic genotyping of loci associated with VMD or RP.
CaseMethod1: Screening of IMPG1 using either gene panel testing or exome sequencing
CaseMethod2: Sanger sequencing-based confirmation
CaseGenotypingMethod: Genotyping is not entirely clear but has at least included panel-based analysis of the IMPG1 locus and Sanger sequencing-based confirmation.
Variant: The proband harbors the NM_001563.4:c.2083G>T (p.Glu695Ter) variant in the heterozygous state.
CAID: CA364770054
gnomAD: This variant is not found in gnomAD v2.1.1.
VariantEvidence: NM_001563.4:c.2083G>T (p.Glu695Ter) is a nonsense variant in exon 15 of 17, which is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 13% of the protein product.
CaseAddInfo: The patient's brother is an unaffected carrier of the variant.
CasePMIDs: N/A
Combined NGS Approaches Identify Mutations in the Intraflagellar Transport Gene IFT140 in Skeletal Ciliopathies with Early Progressive Kidney Disease
PMID: 23418020
Gene: IFT140
HGNC: 29077
Disease: short-rib thoracic dysplasia 9 with or without polydactyly
MONDO: 0009964
InheritancePattern: Autosomal Recessive
Prevalence: The overall prevalence of short-rib thoracic dysplasia is estimated to be between 1 in 100,000 and 1 in 130,000 births (PMID: 931421).
Penetrance: Disease caused by biallelic IFT140 variants appears to be fully penetrant.
Mutations in GPR143/OA1 and ABCA4 Inform Interpretations of Short-Wavelength and Near-Infrared Fundus Autofluorescence
PMID: 29847651
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
RP
FamilyLabel: van_Huet_2014_Family_B, ethnic origin reported as Iraqi Jewish
Family#PresentingHPOs: HP:0011463 (Childhood onset), HP:0000545 (Myopia), HP:0007663 (Reduced visual acuity), HP:0007787 (Posterior subcapsular cataract), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007722 (Retinal pigment epithelial atrophy), HP:0007737 (Bone spicule pigmentation of the retina)
FamilyHPOFreeText: The patient and family members have been diagnosed with retinitis pigmentosa, with macular abnormalities present in all cases.
Family#PresentingNotHPOs: N/A
CountryOrigin: Iraq
Ethnicity: Reported as Iraqi Jewish
Race: Not mentioned
Family#PreviousTesting: Previous genotyping outside of the IMPG2 locus has not been described for this family.
Family#Method1: Sanger sequencing of the 19 exons of the IMPG2 gene
Family#Method2: N/A
Family#GenotypingMethod: Genotyping may have been limited to Sanger sequencing of the 19 exons of the IMPG2 gene, as previous genotyping of other loci has not been described for this family.
Affected: 3
Unaffected: 0
Segregations: Two segregations are reported in the family, with none inconsistent. The family is apparently consanguineous, with the parents being first cousins. The pedigree is shown in Figure 1.
PublishedLOD: N/A
eLOD: 1.20
AddSegregationInfo: N/A
ProbandLabel: van_Huet_2014_Patient_B-II:1
Variant: The affected family members harbor the NM_016247.4(IMPG2):c.635C>G (p.Ser212Ter) variant in the homozygous state.
ClinVar: 3546
gnomAD: This variant was not found in gnomAD v2.1.1.
FamilyAddInfo: The family is reportedly consanguineous, with the parents being first cousins.
FamilyPMIDs: N/A
IMPG2-associated retinitis pigmentosa displays relatively early macular involvement
PMID: 24876279
Gene: IMPG2
HGNC: 18362
Disease: retinitis pigmentosa 56
MONDO: 0013314
InheritancePattern: semi-dominant
Prevalence: Vitelliform macular dystrophy in general is estimated to have a prevalence of 1 in 5,500 (PMID: 27120116).
Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete, while heterozygous carriers of deleterious variants show incomplete penetrance and variable expressivity.
patients
FamilyLabel: van_Huet_2014_Family_A, national origin reported as Dutch
Family#PresentingHPOs: HP:0410280 (Pediatric onset), HP:0007663 (Reduced visual acuity), HP:0007787 (Posterior subcapsular cataract), HP:0011504 (Bull's eye maculopathy), HP:0500087 (Peripapillary atrophy), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007722 (Retinal pigment epithelial atrophy), HP:0007737 (Bone spicule pigmentation of the retina)
FamilyHPOFreeText: The patient and family members have been diagnosed with retinitis pigmentosa, with macular abnormalities present in all cases.
Family#PresentingNotHPOs: N/A
CountryOrigin: Netherlands
Ethnicity: Reported as Dutch
Race: Not mentioned
Family#PreviousTesting: Previous genotyping outside of the IMPG2 locus has not been described for this family.
Family#Method1: Sanger sequencing of the 19 exons of the IMPG2 gene
Family#Method2: N/A
Family#GenotypingMethod: Genotyping may have been limited to Sanger sequencing of the 19 exons of the IMPG2 gene, as previous genotyping of other loci has not been described for this family.
Affected: 3
Unaffected: 3
Segregations: Two segregations are reported in the family, with none inconsistent. The family is apparently not consanguineous. The pedigree is shown in Figure 1.
PublishedLOD: N/A
eLOD: 1.50
AddSegregationInfo: N/A
ProbandLabel: van_Huet_2014_Patient_A-II:1
Variant: The affected family members harbor the NM_016247.4(IMPG2):c.887+430_908+274del variant in the homozygous state.
ClinVar: 3547
gnomAD: This variant was not found in gnomAD v2.1.1.
FamilyAddInfo: Despite the homozygous state of the variant, the family is reportedly not consanguineous.
FamilyPMIDs: N/A
nherited retinal disease
Case#: van_Huet_2014_Patient_F-II:2, female, age 10 years at time of onset, age 32 at the time of report, national origin reported as from Pakistan
CasePresentingHPOs: HP:0410280 (Pediatric onset), HP:0000662 (Nyctalopia), HP:0000545 (Myopia), HP:0007663 (Reduced visual acuity), HP:0011504 (Bull's eye maculopathy), HP:0100014 (Epiretinal membrane), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0000546 (Retinal degeneration), HP:0007737 (Bone spicule pigmentation of the retina)
CaseHPOFreeText: The patient and her family members have been diagnosed with retinitis pigmentosa, with macular abnormalities present in all cases.
CaseNotHPOs: HP:0000517 (Abnormal lens morphology, such as cataract)
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous genotyping outside of the IMPG2 locus has not been described for this family.
CaseMethod1: Sanger sequencing of the 19 exons of the IMPG2 gene
CaseMethod2: N/A
CaseGenotypingMethod: Genotyping may have been limited to Sanger sequencing of the 19 exons of the IMPG2 gene, as previous genotyping of other loci has not been described for this family.
Variant: The affected family members harbor the NM_016247.4(IMPG2):c.1680T>A (p.Tyr560Ter) variant in the homozygous state.
ClinVar: 437938
gnomAD: This variant was not found in gnomAD v2.1.1.
VariantEvidence: The NM_016247.4(IMPG2):c.1680T>A (p.Tyr560Ter) variant is a nonsense variant in exon 13 of 19 that is predicted to lead to nonsense mediated decay or at least to C-terminal truncation of 55% of the protein product.
CaseAddInfo: The family is reportedly consanguineous, with the parents being first cousins. The proband has an affected brother and an affected mother who have the same genotype, as well as a heterozygous carrier father.
CasePMIDs: PMID: 20673862
OCT angiography in the management of choroidal neovascular membrane secondary to Sorsby fundus dystrophy
PMID: 27587748
Gene: TIMP3
HGNC: 11822
Disease: Sorsby fundus dystrophy (SFD), also known as Sorsby's fundus dystrophy, Sorsby pseudoinflammatory fundus dystrophy, or hemorrhagic macular dystrophy
MONDO: 0007640
InheritancePattern: Autosomal Dominant
Prevalence: Estimated at 1 in 220,000 (PMID: 28847738)
Penetrance: Fully penetrant, onset between the third and sixth decades of life
In family B, a G-to-T transversion (ORF15+1176G>T; Fig. 2B ) resulted in a nonsense mutation (G392X).
Case#: Ebenezer_2005_Family_B_Patient_IV:11, male, age 44, family origin reported to be British
CasePresentingHPOs: HP:0003581 (Adult onset), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude), HP:0000662 (Nyctalopia), HP:0007663 (Reduced visual acuity), HP:0000613 (Photophobia), HP:0000545 (Myopia), HP:0000483 (Astigmatism), HP:0007803 (Monochromacy), HP:0007722 (Retinal pigment epithelial atrophy), HP:0025159 (Hypoautofluorescent retinal lesion), HP:0007814 (Retinal pigment epithelial mottling)
CaseHPOFreeText: The proband has been diagnosed with progressive retinal degeneration / cone-rod dystrophy, with the family exhibiting an X-linked pattern of inheritance.
CaseNotHPOs: HP:0000639 (Nystagmus)
CaseNotHPOFreeText: N/A
CasePreviousTesting: The proband and family members were not genotyped outside of the RPGR locus.
CaseMethod1: Sanger sequencing of exon 15 of RPGR
CaseMethod2: N/A
CaseGenotypingMethod: The proband and family members were genotyped by Sanger sequencing of exon 15 of RPGR, but not by genome-wide methods.
Variant: The proband harbors the NM_001034853.2(RPGR):c.2929G>T (p.Gly977Ter) variant in the hemizygous state.
ClinVar: 9918
gnomAD: The variant was not found in gnomAD v.2.1.1.
VariantEvidence: NM_001034853.2(RPGR):c.2929G>T (p.Gly977Ter) is a nonsense variant in the final exon (exon 15) that is not predicted to trigger nonsense-mediated decay, but disrupts ~15% of the C-terminus of the protein product.
CaseAddInfo: The proband is a member of Family B (shown in Figure 1), which includes four other affected genotype-positive males and as well as four carrier females who showed reduced visual acuity and golden tapetal reflex.
CasePMIDs: N/A
In family A, two consecutive substitutions were identified in ORF15+A1094C G1095T (Fig. 2A)that created a premature stop codon that was predicted to result in a truncated protein (E364D/E365X).
Case#: Ebenezer_2005_Family_A_Patient_III.4, male, age not specified, family origin reported to be British
CasePresentingHPOs: HP:0025710 (Late young adult onset), HP:0000662 (Nyctalopia), HP:0007663 (Reduced visual acuity), HP:0000613 (Photophobia), HP:0007803 (Monochromacy), HP:0031624 (Moderate myopia), HP:0001103 (Abnormal macular morphology), HP:0000533 (Chorioretinal atrophy), HP:0500087 (Peripapillary atrophy), HP:0025159 (Hypoautofluorescent retinal lesion), HP:0030844 (Undetectable pattern electroretinogram), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude)
CaseHPOFreeText: The proband has been diagnosed with retinitis pigmentosa, with the family exhibiting an X-linked pattern of inheritance. Cone ERG was more severely reduced than rod ERG.
CaseNotHPOs: HP:0007769 (Peripheral retinal degeneration), HP:0000639 (Nystagmus)
CaseNotHPOFreeText: N/A
CasePreviousTesting: The proband and family members were not genotyped outside of the RPGR locus.
CaseMethod1: Sanger sequencing of exon 15 of RPGR
CaseMethod2: N/A
CaseGenotypingMethod: The proband and family members were genotyped by Sanger sequencing of exon 15 of RPGR, but not by genome-wide methods.
Variant: The proband harbors the NM_001034853.2(RPGR):c.2847_2848inv (p.Glu949_Glu950delinsAspTer) variant in the hemizygous state.
ClinVar: 9917
gnomAD: The variant was not found in gnomAD v.2.1.1.
VariantEvidence: NM_001034853.2(RPGR):c.2847_2848inv (p.Glu949_Glu950delinsAspTer) is an indel in the final exon (exon 15) that introduces a premature stop codon. Although it is not predicted to trigger nonsense-mediated decay, it at least disrupts ~18% of the C-terminus of the protein product.
CaseAddInfo: The proband is a member of Family A (shown in Figure 1), which includes four other affected genotype-positive males and four carrier females who showed RPE abnormalities.
CasePMIDs: N/A
Cardiovascular actions of DOPA mediated by the gene product of ocular albinism 1
PMID: 25185585
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
Microarray-Based Mutation Detection and Phenotypic Characterization of Patients with Leber Congenital Amaurosis
PMID: 16505055
Gene: GUCY2D
HGNC: 4689
Disease: Leber congenital amaurosis 1
MONDO: 0008764
InheritancePattern: Autosomal Recessive
Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by GUCY2D variants is between 10% and 20% (PMID: 10951519). Thus, the prevalence of Leber congenital amaurosis 1 is between 1 in 165,000 and 1 in 1,000,000.
Penetrance: Fully penetrant, with onset in neonates or in infancy
To study the pathogenic effect of the c.1430A>G mutation, we introduced this point mutation into the mouse genome via CRISPR/Cas9-mediated mutagenesis
ExperimentName: Variant knock-in to the mouse Rpe65 locus triggers aberrant mRNA splicing.
NonHumanModel: Mus musculus
GeneAlteration: A substitution equivalent to the human NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant was knocked into the mouse Rpe65 locus by CRISPR/Cas9-based editing.
ModelPhenotype: HP:0000479 (Abnormal retinal morphology), HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0030483 (Reduced amplitude of dark-adapted bright flash electroretinogram a-wave), Retinal thinning HP:0030329
HumanPhenotype: HP:0000662 (Nyctalopia), HP:0007688 (Undetectable light- and dark-adapted electroretinogram), HP:0001098 (Abnormal fundus morphology), HP:0000529 (Progressive visual loss)
ModelEvidence: Despite normal 11-cis retinal levels (Figure 3E), the heterozygous knock-in animals exhibit abnormal accumulation of retinyl esters (Figure 3F), recapitulating a key molecular defect of the human patients. The homozygous (but not heterozygous) knock-in animals also exhibit vacuole formation in the outer segment adjacent to the retinal pigment epithelium (Figure 3B) and abnormalities on dark-adapted ERG indicative of slower recovery of rod function (Figures 4A, 4B) and cone function (Figure 5D) as well as reduced retinal thickness (Figure 5A) after long-term chronic visual pigment bleaching.
ModelVariant: The model knocks the NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant (ClinVar:750796) into the mouse Rpe65 locus.
Mutations in IMPG1 Cause Vitelliform Macular Dystrophies
PMID: 23993198
Gene: IMPG1
HGNC: 6055
Disease: vitelliform macular dystrophy 4
MONDO: 0014508
InheritancePattern: semi-dominant
Prevalence: Vitelliform macular dystrophy in general is estimated to have a prevalence of 1 in 5,500 (PMID: 27120116).
Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete, while heterozygous carriers of deleterious variants show incomplete penetrance and variable expressivity.
In the consanguineous Italian family NA1863, we found that the affected brother II:1 and the affected sister II:2 were homozygous for the splice-site mutation c.807+1G>T in intron 7, which was absent from the human SNP databases, whereas the asymptomatic parents were each heterozygous for the mutation (Figure 4A). In affected individuals of families NAL69 and NA1863, the EOG Arden ratio was moderately decreased (Table 1). During fundus examination, some asymptomatic heterozygous carriers were found to have minor changes. In family NAL69, although the daughter, III:2, was normal, the son, III:1, showed a slight defect in the line between the inner and outer segments in the nasal parafovea of the left eye. In family NA1863, fundus examination showed that the parents had tiny extramacular deposits (Figure 2). This suggests that the c.461T>C and c.807+1G>T changes could be sufficient to cause subclinical retinal abnormalities and exert a mild pathogenic effect at the heterozygous state. Yet, because the macular vitelliform disc with decreased visual acuity (Table 1) was present only in the individuals who were either compound heterozygous (family NAL69) or homozygous (family NA1863), it is likely that the disease in these two families segregated as an autosomal-recessive trait.
Case#: Manes_2013_Family_NA1863_Proband_II:1, male, age between 25 and 45 years at time of report, national origin reported as Italian
CasePresentingHPOs: HP:0007677 (Vitelliform-like macular lesions), HP:0030631 (Hyperautofluorescent macular lesion), HP:0008179 (Decreased Arden ratio of electrooculogram, specifically 1.53 and 1.61 in each eye), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude)
CaseHPOFreeText: The patient has been diagnosed with vitelliform macular dystrophy, and has very mildly reduced visual acuity (20/22).
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous testing appears to have been limited to Sanger sequencing-based screening of exon 7 of IMPG1.
CaseMethod1: Sanger sequencing of the 17 exons and flanking intronic sequences
CaseMethod2: N/A
CaseGenotypingMethod: Genotyping appears to have included Sanger-based sequencing of the 17 exons and intronic flanking sequences of the IMPG1 locus.
Variant: The proband harbors the NM_001563.4(IMPG1):c.807+1G>T variant in the homozygous state.
ClinVar: 162134
gnomAD: The NM_001563.4(IMPG1):c.807+1G>T variant was found in gnomAD v2.1.1 at a frequency of 0.000008855 (1/112932) in the European non-Finnish population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/6-76728434-C-A
VariantEvidence: NM_001563.4(IMPG1):c.807+1G>T is a canonical splice site variant in intron 7 that does not have evidence confirming an impact on the gene product.
CaseAddInfo: The proband has a similarly affected younger sister who shares the same genotype. Parents are clinically unaffected heterozygous carriers but each harbor tiny extramacular deposits in the fundus. Consanguinity is reported in this family.
CasePMIDs: N/A
To determine the subcellular localization of Rp1L1 in rods, we double stained Rp1L1 and rhodopsin, Rp1, or γ-tubulin in dissociated OS preparations (Fig. 2B). Rhodopsin localizes to OS discs, Rp1 localizes to the axoneme of the basal OS (Zhao et al., 2003; Liu et al., 2004), and γ-tubulin localizes to the basal bodies of the CCs (Hong et al., 2001). We found that Rp1L1 localized to the axoneme of both the OS and CCs but not to the axoneme of the IS or on the basal bodies (Figs. 1E, 2B). Recent photoreceptor sensory cilium complex proteome revealed Rp1L1 expression in the OS but not in the IS, consistent with our observations (Liu et al., 2007). Furthermore, Rp1L1 coexisted with Rp1 only in the OS axoneme but not in the CCs; Rp1L1 and Rp1 appeared localized along the entire length of OS axoneme but were more concentrated at the basal third OS, consistent with previous findings (Fig. 2B, bottom) (Zhao et al., 2003; Liu et al., 2004). To determine whether Rp1L1 was colocalized with microtubules in the axoneme, we stained Rp1L1 in retinal sections with α-acetylated tubulin, which is a marker of polymerized microtubules, including those of the axoneme (Fig. 2C). All Rp1L1 signals were colocalized with axoneme-positive signals. Only a small amount of α-acetylated tubulin-positive axoneme did not appear to include Rp1L1. These were probably the axonemes of cones, which lack Rp1L1 (Fig. 2C, long arrowhead). These findings suggest that both Rp1L1 and Rp1 are expressed in the rod photoreceptor axoneme.
Selection B- Gene function is consistent with phenotype.
ExperimentName: RP1L1 protein localizes to the axoneme of the outer segment of rod photoreceptor cells, but not to the connecting cilium, inner segment, or basal bodies (and from cone cells altogether).
GOterm: GO:0120200 (rod photoreceptor outer segment)
FunctionalEvidence: Immunofluorescent staining of Rp1l1 was performed in retinal sections, with staining of rhodopsin, Rp1, and gamma-tubulin for comparison (Figures 1E, 2A, 2B, 2C).
FunctionalHPO: Macular dystrophy HP:0007754, Reduced visual acuity HP:0007663
Essential and Synergistic Roles of RP1 and RP1L1 in Rod Photoreceptor Axoneme and Retinitis Pigmentosa
PMID: 19657028
Gene: RP1L1
HGNC: 15946
Disease: occult macular dystrophy
MONDO: 0013316
InheritancePattern: autosomal dominant
Prevalence: The prevalence of occult macular dystrophy is "significantly less than one in 10,000 or 100,000 (https://www.reviewofoptometry.com/article/the-best-is-yet-to-come-feb).
Penetrance: The disease is known to be incompletely penetrant in family members carrying the heterozygous p.Arg45Trp variant (PMID: 20826268).
affected members
FamilyLabel: Weber_1994_Family_B
Family#PresentingHPOs: HP:0030506 (Yellow/white lesions of the retina), HP:0030604 (Abnormal fundus fluorescein angiography), HP:0011506 (Choroidal neovascularization), HP:0000533 (Chorioretinal atrophy), HP:0200070 (Peripheral retinal atrophy)
FamilyHPOFreeText: Yellow/white lesions were present within fundus specifically. Angiography showed mottled hypofluorescence. Chorioretinal atrophy was described as showing peripheral progression.
FamilyNotHPOs: N/A
CountryOrigin: Canada (PMID:7920634), genealogy indicating Irish descent (PMID: 2695876)
Family#PreviousTesting: Linkage analysis using short tandem repeat markers derived from genomic regions shown to contain loci involved in macular degeneration (PMID:7920634).
Family#GenotypingMethod: Sanger sequencing of Weber_1994_Family_B_patient_V-1
Affected: 1
Unaffected: 1
Segregations: N/A
PublishedLOD: A multipoint LOD Score of 7.43 was published for the interval between tandem repeat markers D22S275 and D22S274 on chromosome 22q13, a region that includes the TIMP3 locus (PMID:7920634).
eLOD: Insufficient information available
AddSegregationInfo: N/A
ProbandLabel: Weber_1994_Family_B_patient_V-1
Variant: The variant is NM_000362.5(TIMP3):c.610A>T, p.Ser204Cys
ClinVar: 12676
gnomAD: Variant is absent from gnomAD.
FamilyAddInfo: Variant was first referred to in PMID:7894485 as "Ser181Cys" but encodes Ser204Cys in the updated polypeptide sequence. A more detailed pedigree is available from an earlier publication (PMID:7920634), but genotyping was not performed at that time, resulting in a lack of segregation data.
FamilyPMIDs: PMID:2695876, PMID:7920634
identified point mutations
Case: Weber_1994_Family_B_Patient_V-1, male, country of origin Canada (PMID:7920634), genealogy indicating Irish descent (PMID: 2695876)
DiseaseAssertion: Sorsby's fundus dystrophy
FamilyInfo:
CasePresentingHPOs: HP:0030506 (Yellow/white lesions of the retina), HP:0030604 (Abnormal fundus fluorescein angiography), HP:0011506 (Choroidal neovascularization), HP:0000533 (Chorioretinal atrophy), HP:0200070 (Peripheral retinal atrophy)
CaseHPOFreeText: Yellow/white lesions were present within fundus specifically. Angiography showed mottled hypofluorescence. Chorioretinal atrophy was described as showing peripheral progression.
CaseNOTHPOs: N/A
CaseNOTHPOFreeText: N/A
CasePreviousTesting: Linkage analysis using short tandem repeat markers derived from genomic regions shown to contain loci involved in macular degeneration (PMID:7920634).
GenotypingMethod: Sanger sequencing
PreviouslyPublished: PMID:2695876, PMID:7920634
SupplementalData: N/A
Variant: The variant is NM_000362.5(TIMP3):c.610A>T, p.Ser204Cys, which was first referred to in PMID:7894485 as "Ser181Cys" (due to the removal of a 23-amino acid N-terminal signal peptide from the polypeptide sequence) but encodes Ser204Cys in the full/updated polypeptide sequence.
ClinVar: 12676
gnomAD: Variant is absent from gnomAD.
VariantEvidence: Variant adds a Cys residue to TIMP3 and is predicted to disrupt tertiary structure.
Sorsby Fundus Dystrophy Mutation in Tissue Inhibitor of Metalloproteinase 3 (TIMP3) promotes Choroidal Neovascularization via a Fibroblast Growth Factor-dependent Mechanism
PMID: 31757977
Gene: TIMP3
HGNC: 11822
Disease: Sorsby fundus dystrophy (SFD), also known as Sorsby's fundus dystrophy, Sorsby pseudoinflammatory fundus dystrophy, or hemorrhagic macular dystrophy
MONDO: 0007640
InheritancePattern: Autosomal Dominant
Prevalence: Estimated at 1 in 220,000 (PMID: 28847738)
Penetrance: Fully penetrant, onset between the third and sixth decades of life
P12 JP01 c.632G>A p.Trp211* c.345_349delCTGGC p.Trp116AlafsTer7
Case#: Georgiou_2024_Family_JP01_Proband_P12, male, reported at age 6 years, family origin reported as from Japan
CasePresentingHPOs: HP:0011003 (High myopia), HP:0030558 (Best corrected visual acuity 0.5 LogMAR)
CaseHPOFreeText: BCVA began at 0.20 logMAR and progressed to 0.57 logMAR.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous genotyping was by either next-generation sequencing panel, whole exome sequencing, or whole genome sequencing, but was unspecified.
CaseMethod1: NGS panel / WES / WGS
CaseMethod2: Sanger sequencing of RBP3
CaseGenotypingMethod: Previous genotyping by either next-generation sequencing panel, whole exome sequencing, or whole genome sequencing was followed by Sanger sequencing of RBP3.
Variant: The individual harbors the NM_002900.3(RBP3):c.632G>A (p.Trp211Ter) and NM_002900.3(RBP3):c.345_349del (p.Trp116AlafsTer7) variants in the compound heterozygous state.
ClinVar ID: 838965
CAID CA2953902720
gnomAD: The NM_002900.3(RBP3):c.345_349del (p.Trp116AlafsTer7) variant was not found in gnomAD version 4.1.1. The NM_002900.3(RBP3):c.632G>A (p.Trp211Ter) variant is found in gnomAD version 4.1.1 at a frequency of 0.00008913 (4 / 44878) in the East Asian population https://gnomad.broadinstitute.org/variant/chr10-47349116-G-A?dataset=gnomad_r4
VariantEvidence: NM_002900.3(RBP3):c.632G>A (p.Trp211Ter) is a nonsense variant within exon 1 of 4 that is predicted to trigger nonsense-mediated decay. NM_002900.3(RBP3):c.345_349del (p.Trp116AlafsTer7) is a frameshift variant within exon 1 of 4 that is predicted to trigger nonsense-mediated decay.
CaseAddInfo: Potential consanguinity within the proband's family has not been commented on.
CasePMIDs: N/A
homozygous 17-bp deletion
Case
EYS, encoding an ortholog of Drosophila spacemaker, is mutated in autosomal recessive retinitis pigmentosa
PMID: 18836446
Gene: EYS
HGNC: 21555
Disease: Retinitis pigmentosa 25
MONDO: MONDO:0011272
InheritancePattern: autosomal recessive
Prevalence: The overall prevalence of retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of retinitis pigmentosa caused by homozygous or compound heterozygous EYS variants is estimated to be 12% in the French population (PMID: 20333770), implying in an overall prevalence between 1 in 25,000 and 1 in 33,000.
Penetrance: The disease appears to be completely penetrant among published families.
RBP4-related eye disease in a Danish family with retinitis pigmentosa and congenital ocular malformations
PMID: 36317196
Homozygosity Mapping Reveals PDE6C Mutations in Patients with Early-Onset Cone Photoreceptor Disorders
PMID: 19615668
Gene: PDE6C
HGNC: 8787
Disease: cone dystrophy 4
MONDO: 0013129
InheritancePattern: recessive
Prevalence: cone dystrophy in general is estimated to have a prevalence of 1 in 40,000 (PMID: 30578485).
Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.
Whole Exome Sequencing Reveals GUCY2D as a Major Gene Associated With Cone and Cone–Rod Dystrophy in Israel
PMID: 25515582
Gene: GUCY2D
HGNC: 4689
Disease: Cone-rod dystrophy 6
MONDO: 0011143
InheritancePattern: Autosomal Dominant
Prevalence: The overall prevalence of cone-rod dystrophy is between 1 in 30,000 and 1 in 40,000 (PMID: 17270046), while the proportion of cone-rod dystrophy caused by GUCY2D variants is between 19% and 23% (PMID: 22183351, PMID: 25515582). Thus, the prevalence of cone-rod dystrophy 6 is between 1 in 130,000 and 1 in 215,000.
Penetrance: Penetrance is age-dependent, with onset between the 1st and 6th decades of life.
nonsense
Case#: Meindl_1996_Family_F50_Proband, male, age not specified, family origin either German or British
CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy)
CaseHPOFreeText: The proband has been diagnosed with retinitis pigmentosa. Disease onset was reported as early.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: The family members previously underwent linkage analysis to map the underlying genetic cause to the region on chromosome Xp21.1 between the CYBB and OTC genes.
CaseMethod1: Hybridization analysis of amplified cDNA fragments from the RPGR locus to look for deletions, and SSCP analysis to look for point mutations
CaseMethod2: Sanger sequencing of the RPGR locus
CaseGenotypingMethod: The family members previously underwent linkage analysis to map the underlying genetic cause to the region on chromosome Xp21.1 between the CYBB and OTC genes. Amplified cDNA fragments from the RPGR locus were then screened by hybridization analysis to look for deletions and SSCP analysis to look for point mutations. The presence of the variant was confirmed by Sanger sequencing of the RPGR locus.
Variant: The affected family members harbor the NM_001034853.2(RPGR):c.581G>A (p.Trp194Ter) variant in the hemizygous state.
ClinVar: 98790
gnomAD: The variant was not found in gnomAD v.2.1.1.
VariantEvidence: NM_001034853.2(RPGR):c.581G>A (p.Trp194Ter) is a nonsense variant predicted to trigger nonsense-mediated decay or to at least disrupt the C-terminal 76% of the protein product.
CaseAddInfo: The proband is a member of Family F50.
CasePMIDs: N/A
Mutations in the gene PDE6C encoding the catalytic subunit of the cone photoreceptor phosphodiesterase in patients with achromatopsia
PMID: 30080950
Gene: PDE6C
HGNC: 8787
Disease: cone dystrophy 4
MONDO: 0013129
InheritancePattern: recessive
Prevalence: cone dystrophy in general is estimated to have a prevalence of 1 in 40,000 (PMID: 30578485).
Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.
To describe a case of symptomatic outer retinal disruption in a patient heterozygous for the p.Leu154Pro interphotoreceptor matrix proteoglycan-1 (IMPG1) mutation implicated in adult-onset foveomacular vitelliform dystrophy. Methods: Observational case report. Results: We describe a case of a 25-year-old female patient with symptomatic scotoma and vision decrease who exhibited bilateral small foveal yellow spots. Optical coherence tomography revealed disorganization and decreased reflectance of the foveal ellipsoid and interdigitation zones in the left eye more than in the right eye. Fundus autofluorescence imaging showed minimal findings, and dye angiography was unrevealing. Multifocal electroretinogram revealed slightly decreased retinal sensitivity in the central retina of the left eye. Genetic testing identified a heterozygous p.Leu154Pro mutation in the IMPG1 gene.
Case#: Gupta_2021_Proband_1, female, age 25 years at time of report, ethnic origin not reported
CasePresentingHPOs: HP:0000575 (Scotoma), HP:0007663 (Reduced visual acuity), HP:0030500 (Yellow/white lesions of the macula, specifically small foveal yellow spots), HP:0030627 (Foveal hyporeflective spaces on macular OCT), HP:0008323 (Abnormal light- and dark-adapted electroretinogram, specifically reduced response in the center of one retina)
CaseHPOFreeText: The patient has been diagnosed with foveomacular vitelliform dystrophy with adult onset.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous testing appears to have included genotyping of the
CaseMethod1:
CaseMethod2:
CaseGenotypingMethod: Genotyping appears to have included
Variant: The proband harbors the NM_001563.4(IMPG1):c.461T>C (p.Leu154Pro) variant in the heterozygous state.
ClinVar: 162136
gnomAD: This variant was found in gnomAD v2.1.1 at a frequency of 0.00007924 (9/113576) in the European non-Finnish population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/6-76744345-A-G
VariantEvidence: NM_001563.4(IMPG1):c.461T>C (p.Leu154Pro) is a missense variant that does not have evidence confirming an impact on the gene product. However, another study has reported apparently unrelated affected patients harboring this variant in the compound heterozygous state (PMID: 23993198), in trans with the NM_001563.4(IMPG1):c.1519C>T (p.Arg507Ter) variant.
CaseAddInfo: The variant is paternally inherited in this case, and the patient's father has been diagnosed with central serous chorioretinopathy but lacks other features of vitelliform macular dystrophy. This indicates that central serous chorioretinopathy is part of the spectrum of monoallelic disease.
CasePMIDs: N/A
A novel homozygous c.67C>T variant in retinol binding protein 4 (RBP4) associated with retinitis pigmentosa and childhood acne vulgaris
PMID: 32323592
The Function of Guanylate Cyclase 1 and Guanylate Cyclase 2 in Rod and Cone Photoreceptors
PMID: 17255100
Gene: GUCY2D
HGNC: 4689
Disease: Leber congenital amaurosis 1
MONDO: 0008764
InheritancePattern: Autosomal Recessive
Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by GUCY2D variants is between 10% and 20% (PMID: 10951519). Thus, the prevalence of Leber congenital amaurosis 1 is between 1 in 165,000 and 1 in 1,000,000.
Penetrance: Fully penetrant, with onset in neonates or in infancy
Prpf4 (pre-mRNA processing factor 4), a key component of spliceosome, plays critical roles in pre-mRNA splicing and its mutations result in retinitis pigmentosa due to photoreceptor defects. In this study, we characterized a zebrafish prpf4t243 mutant harboring a Tol2 transposon-based gene trap cassette in the third intron of the prpf4 gene. Cells in the brain and spinal cord gradually undergo p53-dependent apoptosis after 28 hpf in prpf4t243 mutants, suggesting that a widespread function of prpf4 in neural cell survival. In addition, prpf4 is essential for survival of posterior lateral line primordial (pLLP) cells. prpf4 deficiency perturbs Fgf, Wnt/β-catenin and chemokine signaling pathways and impairs pLLP migration. RNA-Seq analysis suggests that prpf4 deficiency may impair spliceosome assembly, leading to compensatory upregulation of core spliceosomal genes and alteration of pre-mRNA splicing. Taken together, our studies uncover an essential role of prpf4 in pre-mRNA splicing, cell survival and pLLP migration.
Zebrafish harboring an engineered mutation in the prpf4 gene exhibit enhanced brain and spinal cord apoptosis. The mechanism is loss-of-function. Matches the patients?
Dominant mutations in RP1L1 are responsible for occult macular dystrophy
PMID: 20826268
Gene: RP1L1
HGNC: 15946
Disease: occult macular dystrophy
MONDO: 0013316
InheritancePattern: autosomal dominant
Prevalence: The prevalence of occult macular dystrophy is "significantly less than one in 10,000 or 100,000 (https://www.reviewofoptometry.com/article/the-best-is-yet-to-come-feb).
Penetrance: The disease is known to be incompletely penetrant in family members carrying the heterozygous p.Arg45Trp variant (PMID: 20826268).
patients carried compound heterozygous mutations in LRP5
Case#: Qin_2005_patient_8, female, age 14 years at report, national origin reported as Japanese
CasePresentingHPOs: HP:0001103 (Abnormal macular morphology), HP:0004349 (Reduced bone mineral density), HP:0003621 (Juvenile onset)
CaseHPOFreeText: The patient has been diagnosed with simplex FEVR, with bilateral dragged macula.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Genotyping appears to have been limited to the LRP5 and FZD4 loci.
CaseMethod1: Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 and FZD4 loci
CaseMethod2: N/A
CaseGenotypingMethod: Genotyping appears to have been limited to Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 and FZD4 loci.
Variant: The patient harbors the NM_002335.4(LRP5):c.804_813del (p.Gly269fs) and NM_002335.4(LRP5):c.1828G>A (p.Gly610Arg) variants in the compound heterozygous state.
ClinVar: 6295, 6294
gnomAD: The NM_002335.4(LRP5):c.804_813del (p.Gly269fs) variant was not found in gnomAD v2.1.1. The NM_002335.4(LRP5):c.1828G>A (p.Gly610Arg) variant was found in gnomAD v2.1.1 at a frequency of 0.00002644 (3/113484) in the European non-Finnish population https://gnomad.broadinstitute.org/variant/11-68174018-G-A
VariantEvidence: NM_002335.4(LRP5):c.1828G>A (p.Gly610Arg) is a missense variant in exon 9 that does not have experimental evidence of an impact on the protein product. NM_002335.4(LRP5):c.804_813del (p.Gly269fs) is a frameshift variant in exon 4 of 23 that is predicted to trigger nonsense-mediated decay or to at least disrupt the C-terminal 83% of the protein product.
CaseAddInfo: The patient has no family history of FEVR in her parents and brother, although bone mineral density was reduced in both parents. The mother is a carrier for p.Gly610Arg, while the father and brother are heterozygous for p.G268fsX272.
CasePMIDs: N/A
Identification of a homozygous BBS7 frameshift mutation in two (related) Chinese Miao families with Bardet-Biedl Syndrome
PMID: 30839500
Gene: BBS7
HGNC: 18758
Disease: Bardet-Biedl syndrome 7
MONDO: 0014435
InheritancePattern: autosomal recessive
Prevalence: The prevalence of BBS7 variants among Bardet-Biedl syndrome cohorts has been reported at 4.2% (PMID: 19402160), while the prevalence of Bardet-Biedl syndrome overall has been estimated between 1 in 13,500 and 1 in 160,000 live births, depending on the population (PMID: 22713813).
Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.
The GC-E gene (Gucy2e) from the mouse strain 129/SvJ was used to construct a targeting vector. A neomycin-resistance gene cassette replaced a portion of exon 5, which codes for the transmembrane region, leaving a coding sequence that could yield only a truncated protein (see Fig.1a).
ExperimentName: Phenotypes from homozygous Gucy2e mouse knockout model
NonHumanModel: Mus musculus
GeneAlteration: The mouse Gucy2e gene was disrupted by the introduction of a neomycin-resistance gene cassette into exon 5, resulting in a truncated protein lacking its transmembrane domain (PMID: 10407028). The effects of this knockout were studied in both heterozygous and homozygous states.
ModelPhenotype: HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0030465 (Undetectable light-adapted electroretinogram), HP:0008020 (Cone dystrophy)
HumanPhenotype: HP:0007663 (Reduced visual acuity), HP:0007688 (Undetectable light- and dark-adapted electroretinogram), HP:0007703 (Abnormality of retinal pigmentation)
ModelEvidence: By 5 weeks of age, Gucy2e-deficient animals exhibit dramatic reduction/degeneration of cones in the outer nuclear layer (Fig. 3a–d). This was confirmed by disappearance of labeling of cone cell nuclei by the lectin PNA (Fig. 3g-h). ERG showed that rod a-wave and b-wave were markedly reduced by 1 month of age, while cone responses were nondetectable as early as 2 months of age (Fig. 4a-b). A proposed explanation for the absence of more severe rod defects is the continued presence of the Gucy2f paralog in this mouse model, which may compensate for the absence of Gucy2e function in rod cells specifically. This hypothesis has been confirmed in a subsequent double-knockout model (PMID: 17255100)
ModelVariant: The mouse model disrupts the expression of the endogenous GC1 protein product but does not feature knock-in of a variant from a human patient.
Disruption of a Retinal Guanylyl Cyclase Gene Leads to Cone-Specific Dystrophy and Paradoxical Rod Behavior
PMID: 10407028
Gene: GUCY2D
HGNC: 4689
Disease: Leber congenital amaurosis 1
MONDO: 0008764
InheritancePattern: Autosomal Recessive
Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by GUCY2D variants is between 10% and 20% (PMID: 10951519). Thus, the prevalence of Leber congenital amaurosis 1 is between 1 in 165,000 and 1 in 1,000,000.
Penetrance: Fully penetrant, with onset in neonates or in infancy
Cauli: A Mouse Strain with an Ift140 Mutation That Results in a Skeletal Ciliopathy Modelling Jeune Syndrome
PMID: 24009529
Gene: IFT140
HGNC: 29077
Disease: Short-rib thoracic dysplasia 9 with or without polydactyly
MONDO: 0009964
InheritancePattern: autosomal recessive
Prevalence: Within the lumped disease entity for this curation, the most prevalent form may be retinitis pigmentosa. The prevalence of Saldino-Mainzer syndrome (one of the synonyms of Short-rib thoracic dysplasia 9) is less than 1 in 1,000,000. The prevalence of Leber congenital amaurosis cases caused by IFT140 variants (PMID: 26216056) is calculated to be less than 1 in 3,000,000. Although IFT140 variants are estimated to be responsible for less than 2% of RP, the prevalence of the overall disorder at 1 in 3,000 or 1 in 4,000 means the frequency of these cases could potentially be higher than 1 in 1,000,000.
Penetrance: Known variants for this lumped disease entity appear to be completely penetrant, with highly variable phenotypes and age of onset. On the other hand, the split disease entity caused by monoallelic IFT140 variants appears to have incomplete penetrance.
A2885-II1–II2 (AKK65)
Case#: Harville_2010_Patient_A2885–II2, sex and age not reported, family origin reportedly from Saudi Arabia
CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy), HP:0010442 (Polydactyly), HP:0001513 (Obesity), HP:0000077 (Abnormality of the kidney), HP:0001249 (Intellectual disability), HP:0004322 (Short stature), HP:0001263 (Global developmental delay), HP:0000823 (Delayed puberty)
CaseHPOFreeText: The proband has an initial clinical diagnosis of Bardet-Biedl syndrome.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: The proband was initially subjected to homozygosity mapping to identify parts of the genome to search for the basis of recessive disease.
CaseMethod1: homozygosity mapping
CaseMethod2: Sanger sequencing of the exons of any of the 14 BBS-associated loci (BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, TRIM32, BBS12, MKS1, and CEP290) that showed homozygosity.
CaseGenotypingMethod: The proband was initially subjected to homozygosity mapping to identify parts of the genome to search for the basis of recessive disease. This was followed by Sanger sequencing of the exons of any of the 14 BBS-associated loci (BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, TRIM32, BBS12, MKS1, and CEP290) that showed homozygosity.
Variant: The proband harbors the NM_024649.5(BBS1):c.124+1G>A variant in the homozygous state.
ClinVar ID: 557428
gnomAD: The NM_024649.5(BBS1):c.124+1G>A variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_024649.5(BBS1):c.124+1G>A is a canonical splice site variant in intron 2 that is predicted but not confirmed to disrupt BBS1 splicing.
CaseAddInfo: The proband's family is reportedly consanguineous and includes a similarly affected sibling sharing the same homozygous genotype.
CasePMIDs: N/A
Biochemical Characterization S156C, G166C, and S181C SFD Mutations
NonPatientCell: COS-7 cells (EFO:0001643, CLO:0002597)
GeneFunction: GO:0008191 (metalloendopeptidase inhibitor activity), GO:0046872 (metal ion binding), GO:0002020 (protease binding), GO:0005615 (active in extracellular space), GO:0031012 (active in extracellular matrix)
GeneAlteration: TIMP3 expression constructs encoding the "Ser181Cys", "Ser156Cys", "Gly166Cys", and "Glu139X" variants (officially referred to as the Ser204Cys, Ser179Cys, Gly189Cys, and Glu162X variants) were generated by PCR-based mutagenesis of the wild-type TIMP-3-pCI.neo construct.
FunctionalEvidence: The TIMP3 variants were exogenously expressed in COS-7 cells alongside the wild-type control. Reverse zymography of extracellular matrix from these cells revealed the presence of dimeric species with metalloproteinase inhibitory activity in the variant-transfected conditions, but not in the wild-type control (Figure 3). These bands were confirmed to be TIMP3 by immunoblotting the extracellular matrix from these cells under non-reducing conditions, as they disappeared under reducing conditions (Figure 4). Under reducing conditions, the variant-transfected cells show higher levels of monomeric TIMP3 relative to the wild-type control (Figure 4b), but it should be noted that the wild-type control is depicted on a separate blot / exposure. The dimerized Glu162X variant is difficult to distinguish from other full-length monomeric species, but appears to be present as well (Figure 5).
FAVariants: Variants used were equivalent to NM_000362.5(TIMP3):c.610A>T (p.Ser204Cys) (ClinVarID:12676), NM_000362.5(TIMP3):c.536C>G, (p.Ser179Cys) (ClinVarID:12678), NM_000362.5(TIMP3):c.565G>T (p.Gly189Cys) (ClinVarID:12679), and NM_000362.5(TIMP3):c.484G>T (p.Glu162X) (ClinVarID:12680).
Clinical and whole exome sequencing findings in children from Yunnan Yi minority ethnic group with retinitis pigmentosa: two case reports
PMID: 37264419
Gene: PRPF4
HGNC: 17349
Disease: retinitis pigmentosa 70
MONDO: 0014400
InheritancePattern: autosomal dominant
Prevalence: The overall prevalence of retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of retinitis pigmentosa with a dominant mode of inheritance is estimated to be 15-35% (between 1 in 8,500 and 1 in 27,000). The proportion of that incidence made up by the specific form caused by variants in PRPF4 is not clear.
Penetrance: Known disease-causing alleles appear to be incompletely penetrant (PMID: 25383878).
families
FamilyLabel: Tabata_1998_Family_Ue
Family#PresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0025094 (Disciform macular scar)
FamilyHPOFreeText: Onset of decreased central vision was seen in the 8th decade of life (between the ages of 71 and 75).
FamilyNotHPOs: HP:0007994 (Peripheral visual field loss)
FamilyNotHPOFreeText: Although central vision was decreased, peripheral fundi remained uninvolved.
CountryOrigin: Japan
Family#PreviousTesting: PCR-based heteroduplex analysis using gel electophoresis
Family#GenotypingMethod: Sanger sequencing
Affected: 3
Unaffected: 0
Segregations: N/A
PublishedLOD: N/A
eLOD: Insufficient information available
AddSegregationInfo: N/A
ProbandLabel: Tabata_1998_Family_Ue_patient_1
Variant: NM_000362.5:c.439-2dup (TIMP3) is predicted to disrupt a splice acceptor site at the junction of intron 4 and exon 5.
CAID: CA1139771334
gnomAD: Variant is absent from gnomAD.
FamilyAddInfo: While Family Ue and Family Ch are two distinct families, united by the NM_000362.5:c.439-2dup (TIMP3) variant harbored by their affected family members, they share a geographical place of origin within Japan (PMID:9760202).
FamilyPMIDs: N/A
RPGR mutation associated with retinitis pigmentosa, impaired hearing, and sinorespiratory infections
PMID: 12920075
Gene: RPGR
HGNC: 10295
Disease: RPGR-related retinopathy
MONDO: MONDO:0100437
InheritancePattern: X-linked
Prevalence: The prevalence of RPGR-related retinopathy is calculated to be approximately 1 in 214,000, based on the known incidence of retinitis pigmentosa at 1 in 3,000, the proportion of retinitis pigmentposa that is X-linked at 20%, and the proportion of X-linked retinitis pigmentosa that is RPGR-associated at 70% (PMID: 34985506).
Penetrance: Penetrance is nearly 100% in hemizygous males but is incomplete and dependent upon the variant in heterozygous female carriers.
The neuronal ceroid lipofuscinosis protein CLN5: new insights into cellular maturation, transport, and consequences of mutations
PMID: 20052765
Gene: CLN5
HGNC: 2076
Disease: Ceroid lipofuscinosis, neuronal, 5 (also known as Finnish variant late infantile neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis late infantile Finnish variant, or Finnish vLINCL)
MONDO: 0009745
InheritancePattern: Autosomal Recessive
Prevalence: Unknown, but part of a larger group of NCL disorders with a collective prevalence between 1 in 12,500 (PMID:9662406) and 1 in 100,000 (PMID:23374165)
Penetrance: Fully penetrant, with onset often in the late infantile period but in some cases during early adulthood or even as late as in the 6th decade of life
GUCY2D mutations in a Chinese cohort with autosomal dominant cone or cone–rod dystrophies
PMID: 26298565
Gene: GUCY2D
HGNC: 4689
Disease: Cone-rod dystrophy 6
MONDO: 0011143
InheritancePattern: Autosomal Dominant
Prevalence: The overall prevalence of cone-rod dystrophy is between 1 in 30,000 and 1 in 40,000 (PMID: 17270046), while the proportion of cone-rod dystrophy caused by GUCY2D variants is between 19% and 23% (PMID: 22183351, PMID: 25515582). Thus, the prevalence of cone-rod dystrophy 6 is between 1 in 130,000 and 1 in 215,000.
Penetrance: Penetrance is age-dependent, with onset between the 1st and 6th decades of life.
Extracellular matrix component expression in human pluripotent stem cell-derived retinal organoids recapitulates retinogenesis in vivo and reveals an important role for IMPG1 and CD44 in the development of photoreceptors and interphotoreceptor matrix
PMID: 29777959
Gene: IMPG1
HGNC: 6055
Disease: vitelliform macular dystrophy 4
MONDO: 0014508
InheritancePattern: semi-dominant
Prevalence: Vitelliform macular dystrophy in general is estimated to have a prevalence of 1 in 5,500 (PMID: 27120116).
Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete, while heterozygous carriers of deleterious variants show incomplete penetrance and variable expressivity.
Clinical features of a novel TIMP-3 mutation causing Sorsby's fundus dystrophy: implications for disease mechanism
PMID: 11734514
Gene: TIMP3
HGNC: 11822
Disease: Sorsby fundus dystrophy (SFD), also known as Sorsby's fundus dystrophy, Sorsby pseudoinflammatory fundus dystrophy, or hemorrhagic macular dystrophy
MONDO: 0007640
InheritancePattern: Autosomal Dominant
Prevalence: Estimated at 1 in 220,000 (PMID: 28847738)
Penetrance: Fully penetrant, onset between the third and sixth decades of life
Cone Photoreceptor Function Loss-3, a Novel Mouse Model of Achromatopsia Due to a Mutation in Gnat2
PMID: 17065522
GeneName: GNAT2
HGNC: 4394
Disease: achromatopsia 4
MonDO ID: MONDO_0013465
Inheritance: autosomal recessive
419532
This article studies mice known as rds with homozygous disruption of the Prph2 locus. Phenotypes include progressive degeneration of retina, absence of rods at age 7-10 months, and reduction of the number of rows of photosensitive cell nuclei to only 1-4 rows. The mouse has been previously published (PMID: 705766).
Whole Exome Sequencing Analysis Identifies Mutations in LRP5 in Indian Families with Familial Exudative Vitreoretinopathy
PMID: 27228167
Gene: LRP5
HGNC: 6697
Disease: osteoporosis-pseudoglioma syndrome
MONDO: 0009820
InheritancePattern: autosomal recessive
Prevalence: osteoporosis-pseudoglioma syndrome is estimated to occur in 1 out of every 2,000,000 live births.
Penetrance: The penetrance of the phenotype among homozygous or compound heterozygous cases appears to be complete, while heterozygous carriers of deleterious variants appear to be mildly affected.
Osteoporosis-pseudoglioma syndrome, a disorder affecting skeletal strength and vision, is assigned to chromosome region 11q12-13
PMID: 8659519
Gene: LRP5
HGNC: 6697
Disease: osteoporosis-pseudoglioma syndrome
MONDO: 0009820
InheritancePattern: autosomal recessive
Prevalence: osteoporosis-pseudoglioma syndrome is estimated to occur in 1 out of every 2,000,000 live births.
Penetrance: The penetrance of the phenotype among homozygous or compound heterozygous cases appears to be complete, while heterozygous carriers of deleterious variants appear to be mildly affected.
As a first step toward determining the cause of OPS, we utilized a combination of traditional linkage analysis and homozygosity mapping to assign the OPS locus to chromosome region 11q12-13. Mapping was accomplished by analyzing 16 DNA samples (seven affected individuals) from three different consanguineous kindreds.
FamilyLabel: Gong_1996_Three_Families
Family#PresentingHPOs: N/A
FamilyPresentingHPOFreeText: The affected family members have been diagnosed with osteoporosis-pseudoglioma syndrome segregating with an autosomal recessive mode of inheritance. This implies a combination of ophthalmologic and radiographic features, but these have not been described in detail.
FamilyNotHPOs: N/A
FamilyNotHPOFreeText: N/A
CountryOrigin: The three families are reportedly of Finnish, South African, and Italian descent, respectively.
Ethnicity: Not specifically described
Race: Not specifically described
Family#PreviousTesting: Genome-wide linkage mapping with 160 SSRP markers was performed on three different consanguineous kindreds (from Finland, South Africa, and Italy) (fig. 1).
Family#Method1: Genome-wide linkage analysis
Family#Method2: Further linkage analysis with additional markers around a strong candidate marker
Family#GenotypingMethod: Genome-wide linkage mapping with 160 SSRP markers was performed on three different consanguineous kindreds (from Finland, South Africa, and Italy) (Fig. 1). Further linkage testing with additional markers around a strong candidate marker yielded a LOD score of 5.99 for Dl1S987. The region consisted of a 13-cM genetic interval on chromosome 11q12-13.
Affected: 7 genotyped
Unaffected: 5 genotyped
Segregations: 5 segregations are shown by the three pedigrees in Figure 1.
PublishedLOD: 5.99 (for the Dl1S987 marker)
eLOD: N/A
AddSegregationInfo: While only one of the families would individually be eligible for inclusion in segregation evidence using an estimated LOD score, the published LOD score is sufficient for their inclusion.
ProbandLabel: N/A (Probands have been incorporated into the later Gong 2001 publication and will be scored in connection to that article.)
Variant: The affected family members harbor three different variants, each in the homozygous state.
ClinVar: N/A
gnomAD: N/A
VariantEvidence: N/A
FamilyAddInfo: All three families are reportedly consanguineous.
FamilyPMIDs: N/A
The c.554T>C mutation is homozygous in patient 741 and heterozygous in both parents.
Case#: Wang_2013_Proband_741, female, age 30 years at time of report, family origin not reported
CasePresentingHPOs: Retinal dystrophy HP:0000556, Attenuation of retinal blood vessels HP:0007843, Retinal pigment epithelial mottling HP:0007814, Patchy atrophy of the retinal pigment epithelium HP:0007791, Abnormality of macular pigmentation HP:0008002, Perifoveal ring of hyperautofluorescence HP:0030629, Abnormal retinal morphology on macular OCT HP:0030612, Mildly reduced visual acuity HP:0032037, Subretinal deposits HP:0031528
CaseHPOFreeText: The proband has a diagnosis of juvenile retinitis pigmentosa.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: The proband was subjected to capture-based next-generation sequencing panel that included 163 known retinal disease genes.
CaseMethod1: next-generation sequencing panel
CaseMethod2: SNP array and Sanger sequencing of PRPH2
CaseGenotypingMethod: The proband was genotyped by capture-based next-generation sequencing panel that included 163 known retinal disease genes. Sanger sequencing of PRPH2 was subsequently used to confirm the presence of the variant.
Variant: The proband harbors the NM_000322.5(PRPH2):c.554T>C (p.Leu185Pro) variant in the homozygous state.
ClinVar ID: 13165
gnomAD: The NM_000322.5(PRPH2):c.554T>C (p.Leu185Pro) variant is found in gnomAD v4.0.0 at a frequency of 0.00003587 in the European (non-Finnish) population, with 15 alleles / 418142 total alleles (0 homozygotes) https://gnomad.broadinstitute.org/variant/6-42721781-A-G?dataset=gnomad_r4
VariantEvidence: NM_000322.5(PRPH2):c.554T>C (p.Leu185Pro) is a missense variant with mouse knock-in evidence of a disease-causing effect in the heterozygous state (PMID: 11427722). Mouse phenotypes from PMID: 11427722 included reduced amplitude of dark-adapted bright flash electroretinogram a-wave HP:0030483 (Figure 4), Reduced OCT-measured macular thickness HP:0030607 (Figure 2), and immunoblot analysis showing reduced L185P in retinas, indicating instability or reduced transport to the outer segment (Figure 5b). Other experiments from PMID: 11297544 showed that the p.Leu185Pro variant successfully forms dimers but fails to assemble into higher order oligomers, particularly in the absence of wild-type PRPH2 (Figures 3, 5).
CaseAddInfo: The proband's parents are each heterozygous carriers of the variant who appear to be sub-clinically affected. The 56-year-old father showed macular pattern dystrophy with clear foveal changes, but normal visual acuity.
CasePMIDs: N/A
To assess whether mutations in KCNJ13 are a common cause of autosomal recessive retinal dystrophy, we performed bidirectional Sanger sequencing of the entire coding region and intron-exon boundaries of the gene in 333 additional unrelated patients (primer details are listed in Table S2). Among the patients, 132 were affected with recessive LCA or childhood onset retinal dystrophy; this panel was enriched for mutations in novel genes, as the patients' DNA had been screened and excluded for previously reported LCA-causing variants through a microarray chip (LCA Chip, Asper Biotech; 35% mutation detection rate; D.S.M, unpublished data). The remaining 201 individuals were diagnosed with autosomal recessive adult onset rod-cone or cone-rod dystrophy and had unknown molecular diagnosis. A homozygous missense variant (c.722T>C [p.Leu241Pro]) was identified in a patient of white European descent (subject B-3, III-2 in Figure 1A; proband of family B) with a remarkably similar phenotype to that observed in family A. Segregation analysis confirmed heterozygosity for the p.Leu241Pro change in maternal (subject B-1, II-4 in Figure 1A) and paternal (subject B-2, II-5 in Figure 1A) DNA. This sequence change has not been previously reported (dbSNP and 1000 genomes) and was found to be absent from 382 ethnically matched control chromosomes (Human Random Control DNA Panels, Salisbury, UK). Although the patient is not knowingly consanguineous, his parents originate from the same isolated geographic area. It is therefore likely that the homozygous state at this locus is consequent upon the presence of a recent common ancestor.
Case#: Sergouniotis_2011_Proband_B-3, male, age 33 years, family ethnic origin described as European
CasePresentingHPOs: Reduced visual acuity HP:0007663, Constriction of peripheral visual field HP:0001133, Infantile onset HP:0003593, Strabismus HP:0000486, Nystagmus HP:0000639, Progressive night blindness HP:0007675, Moderate myopia HP:0031624, Decreased light- and dark-adapted electroretinogram amplitude HP:0000654, Presenile cataracts HP:0007819, Nummular pigmentation of the fundus HP:0030505, Retinal pigment epithelial loss on macular OCT HP:0030611
CaseHPOFreeText: The proband received a diagnosis of Leber congenital amaurosis. His phenotype is described as similar to the other affected individuals, including "a distinct and unusual retinal appearance and a similar early onset of visual loss, suggesting both impaired retinal development and progressive retinal degeneration, involving both rod and cone pathways". The disease was described as mildly progressive. OCT showed distorted retinal microanatomy even in areas without cell death, possibly indicating disturbance of the early development of the neurosensory retina.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: The proband was previously genotyped by screening for previously-reported LCA-causing variants by microarray chip, with no molecular diagnosis.
CaseMethod1: screening for previously-reported LCA-causing variants by microarray chip
CaseMethod2: Sanger sequencing of the KCNJ13 exons and intron-exon boundaries
CaseGenotypingMethod: The proband was previously genotyped by screening for previously-reported LCA-causing variants by microarray chip, with no molecular diagnosis. Sanger sequencing of the KCNJ13 exons and intron-exon boundaries was subsequently performed.
Variant: The individual is homozygous for the NM_002242.4(KCNJ13):c.722T>C (p.Leu241Pro) variant.
ClinVar: 30332
gnomAD: The variant was not found in gnomAD version 4.1.0.
VariantEvidence: NM_002242.4(KCNJ13):c.722T>C (p.Leu241Pro) is a missense variant that has no experimental evidence in this study but has separately been shown to severely decrease expression and abolish complex glycosylation of KCNJ13 (PMID: 30257863, Figure 10).
CaseAddInfo: The proband's family history is not known to include consanguinity but heterozygous parents originate from the same isolated geographic area.
CasePMIDs: N/A
To examine the in vivo function of BBS7, we generated Bbs7 knockout mice. Bbs7−/− mice show similar phenotypes to other BBS gene mutant mice including retinal degeneration, obesity, ventriculomegaly and male infertility characterized by abnormal spermatozoa flagellar axonemes. Using tissues from Bbs7−/− mice, we show that BBS7 is required for BBSome formation, and that BBS7 and BBS2 depend on each other for protein stability. Although the BBSome serves as a coat complex for ciliary membrane proteins, BBS7 is not required for the localization of ciliary membrane proteins polycystin-1, polycystin-2, or bitter taste receptors, but absence of BBS7 leads to abnormal accumulation of the dopamine D1 receptor to the ciliary membrane, indicating that BBS7 is involved in specific membrane protein localization to cilia.
ExperimentName: Genetically engineered Bbs7 homozygous knockout mouse
NonHumanModel: Mus musculus
GeneAlteration: The model animals harbor a homozygous replacement of Bbs7 exon 5 with a neomycin cassette, resulting in a frameshifted allele confirmed by western blotting to result in a null effect on the gene product.
ModelPhenotype: HP:0000546 (Retinal degeneration), HP:0032558 (Absent sperm flagella), HP:0001513 (Obesity), HP:0002119 (Ventriculomegaly), HP:0003251 (Male infertility), HP:0030609 (Photoreceptor layer loss on macular OCT), HP:0012258 (Abnormal axonemal organization of respiratory motile cilia), HP:0033524 (Abnormal sperm axoneme morphology)
HumanPhenotype: HP:0001956 (Truncal obesity), HP:0000618 (Blindness), HP:0001249 (Intellectual disability), HP:0001631 (Atrial septal defect), HP:0001640 (Cardiomegaly), HP:0100598 (Pulmonary edema), HP:0012584 (Bilateral renal hypoplasia), HP:0004719 (Hyperechogenic kidneys), HP:0003774 (Stage 5 chronic kidney disease), HP:0000580 (Pigmentary retinopathy), HP:0000648 (Optic atrophy), HP:0008043 (Retinal arteriolar constriction), HP:0007737 (Bone spicule pigmentation of the retina), HP:0007754 (Macular dystrophy)
ModelEvidence: This is a genetically engineered mouse model of biallelic Bbs7 disruption. The mutant animals with biallelic Bbs7 disrupion exhibit photoreceptor inner and outer segment loss (Figure 1), ventriculomegaly (Figure 1), reduced number of cilia and shortened cilia in brain tissue (Figure 2), abnormal axonemal structure / microtubule number abnormality in brain cilia (Figures 2F, 2G), lack of sperm flagella (Figure 3), Abnormal sperm axoneme microtubule organization (Figure 3), destabilization /absence of BBS2 in testes (Figure 4), and abnormal accumulation of some ciliary membrane proteins (dopamine D1 receptor, Figure 6) but not others (polycystin-1 or polycystin-2, Figure 5). Kidney cysts and polydactyly were looked for and found to be absent.
ModelVariant: This model did not introduce a disease-associated variant known from an affected human patient, but rather studied a genetically engineered null variant disrupting Bbs7 expression.
Nr2e3-directed transcriptional regulation of genes involved in photoreceptor development and cell-type specific phototransduction
PMID: 19379737
Gene: NR2E3
HGNC: 7974
Disease: enhanced S-cone syndrome
MONDO: 0100288
InheritancePattern: autosomal recessive
Prevalence: The overall prevalence of enhanced S cone syndrome is <1 in 1,000,000 (PMID: 30900587).
Penetrance: The penetrance of enhanced S-cone syndrome has been difficult to determine accurately given the rarity of the condition.
disease-causing
Case#: Gong_2001_Proband_4, no reported gender, age or national origin
CasePresentingHPOs: HP:0004349 (Reduced bone mineral density)
CaseHPOFreeText: The proband has been diagnosed with osteoporosis-pseudoglioma syndrome segregating with an autosomal recessive mode of inheritance. This implies a combination of ophthalmologic and radiographic features, but these have not been described in detail.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Genome-wide linkage mapping with 160 SSRP markers was performed on three different consanguineous kindreds (from Finland, South Africa, and Italy) (fig. 1), but it is not clear whether this proband was a member of one of these kindreds.
CaseMethod1: Linkage analysis with additional markers around a strong candidate marker
CaseMethod2: Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 locus
CaseGenotypingMethod: Genotyping appears to have been limited to Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 locus.
Variant: The patient harbors the NM_002335.4(LRP5):c.2151dup (p.Asp718Ter) variant in the homozygous state.
ClinVar: 6271
gnomAD: The NM_002335.4(LRP5):c.2151dup (p.Asp718Ter) variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_002335.4(LRP5):c.2151dup (p.Asp718Ter) is a nonsense variant in exon 10 out of 23 that is predicted to trigger nonsense-mediated decay or at least to truncate the C-terminal ~56% of the protein product.
CaseAddInfo: The family is reportedly consanguineous.
CasePMIDs: PMID: 8659519
Q853X
Case#: Gong_2001_Proband_5, no reported gender, age or national origin
CasePresentingHPOs: HP:0004349 (Reduced bone mineral density)
CaseHPOFreeText: The proband has been diagnosed with osteoporosis-pseudoglioma syndrome segregating with an autosomal recessive mode of inheritance. This implies a combination of ophthalmologic and radiographic features, but these have not been described in detail.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Genome-wide linkage mapping with 160 SSRP markers was performed on three different consanguineous kindreds (from Finland, South Africa, and Italy) (fig. 1), but it is not clear whether this proband was a member of one of these kindreds.
CaseMethod1: Linkage analysis with additional markers around a strong candidate marker
CaseMethod2: Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 locus
CaseGenotypingMethod: Genotyping appears to have been limited to Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 locus.
Variant: The patient harbors the NM_002335.4(LRP5):c.2557C>T (p.Gln853Ter) variant in the homozygous state.
ClinVar: 6272
gnomAD: The NM_002335.4(LRP5):c.2557C>T (p.Gln853Ter) variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_002335.4(LRP5):c.2557C>T (p.Gln853Ter) is a nonsense variant in exon 12 out of 23 that is predicted to trigger nonsense-mediated decay or at least to truncate the C-terminal ~47% of the protein product. It appears to be stable at the protein level but is not secreted in the exogenous expression system, consistent with loss-of-function rather than dominant negative effect.
CaseAddInfo: The family is reportedly consanguineous.
CasePMIDs: PMID: 8659519
All families carrying the SVA F are of European ancestry: 4 originated from the western part of France (family A, C, E and F), one from the northern part of France (family B)
Case#: Delvallée_2021_Proband_B.II-1, male, age not described, family origin reported as from western France, ancestry reported as European
CasePresentingHPOs: HP:0000556 (Retinal dystrophy), HP:0000639 (Nystagmus), HP:0001162 (Postaxial hand polydactyly), HP:0001156 (Brachydactyly), HP:0001513 (Obesity), HP:0001256 (Intellectual disability, mild), HP:0001270 (Motor delay), HP:0000054 (Micropenis), HP:0000028 (Cryptorchidism)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: The proband was subjected to targeted exome sequencing to detect variants in BBS-related loci.
CaseMethod1: targeted exome sequencing
CaseMethod2: Sanger sequencing of BBS1
CaseGenotypingMethod: The proband was subjected to targeted exome sequencing to detect variants in BBS-related loci, followed by Sanger sequencing of BBS1 to identify the variant and perform segregation analysis within the family.
Variant: The proband harbors the NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) and NM_024649.5(BBS1):c.1214_1215insSVA variants in the compound heterozygous state.
ClinVar ID: 12143, 981241
gnomAD: The NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) variant is found in gnomAD v2.1.1 at a frequency of 0.002773 in the European (non-Finnish) population, with 358 alleles / 129114 total alleles (0 homozygotes) https://gnomad.broadinstitute.org/variant/11-66293652-T-G?dataset=gnomad_r2_1 The NM_024649.5(BBS1):c.1214_1215insSVA was not found in gnomAD v2.1.1.
VariantEvidence: NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) is a missense variant with mouse knock-in evidence of a similar disease-causing effect in the homozygous state (PMID: 18032602). This has not been taken into account in scoring, as the mouse model has been scored separately. However, it has provided a rationale not to down-score for the relatively high gnomAD frequency of this variant. NM_024649.5(BBS1):c.1214_1215insSVA is an indel in exon 13 of 17 that is reported to shift the reading frame and trigger nonsense-mediated decay. Figure 3 confirms the likely occurrences of NMD by indicating that the compound heterozygous probands have approximately 50% of wild-type levels of both BBS1 mRNA and protein.
CaseAddInfo: The proband's family includes two similarly affected brothers sharing the same genotype.
CasePMIDs: N/A
u
Case#: Haider_2000_Proband_2, sex, age, and origin not reported
CasePresentingHPOs: N/A
CaseHPOFreeText: The proband is part of a cohort in which all patients had a diagnosis of enhanced S-cone syndrome, based on electroretinogram and/or psychophysics, as well as optical coherence tomography. Other phenotypes within the cohort members (but not tracked individually) included increased sensitivity to blue light; visual loss, night blindness occurring from early in life, varying degrees of L-cone and M-cone vision, and retinal degeneration.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous genotyping was limited to Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.
CaseMethod1: Sanger sequencing of NR2E3
CaseMethod2: SSCP analysis of PCR products from NR2E3
CaseGenotypingMethod: Genotyping was performed by Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.
Variant: The individual harbors the NM_014249.4(NR2E3):c.200_208del (p.Cys67_Gly69del) variant in the homozygous state.
ClinVarID: 5531
gnomAD: The variant was not found in gnomAD version 4.1.0.
VariantEvidence: NM_014249.4(NR2E3):c.200_208del (p.Cys67_Gly69del) is a short in-frame deletion variant within the zinc finger / DNA-binding domain of NR2E3.
CaseAddInfo: It is not clear whether the proband came from a consanguineous family.
CasePMIDs: N/A
a
Case#: Haider_2000_Proband_4, sex, age, and origin not reported
CasePresentingHPOs: N/A
CaseHPOFreeText: The proband is part of a cohort in which all patients had a diagnosis of enhanced S-cone syndrome, based on electroretinogram and/or psychophysics, as well as optical coherence tomography. Other phenotypes within the cohort members (but not tracked individually) included increased sensitivity to blue light; visual loss, night blindness occurring from early in life, varying degrees of L-cone and M-cone vision, and retinal degeneration.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous genotyping was limited to Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.
CaseMethod1: Sanger sequencing of NR2E3
CaseMethod2: SSCP analysis of PCR products from NR2E3
CaseGenotypingMethod: Genotyping was performed by Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.
Variant: The individual harbors the NM_014249.4(NR2E3):c.227G>A (p.Arg76Gln) variant in the homozygous state.
ClinVarID: 5530
gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.0004046 in the South Asian population (36 alleles / 88,984 total alleles, with 1 homozygote) https://gnomad.broadinstitute.org/variant/chr15-71811591-G-A?dataset=gnomad_r4
VariantEvidence: NM_014249.4(NR2E3):c.227G>A (p.Arg76Gln) is a missense variant within the zinc finger / DNA-binding domain of NR2E3, and occurs at the same amino acid position as another missense substitution reported in the same article.
CaseAddInfo: It is not clear whether the proband came from a consanguineous family.
CasePMIDs: N/A
Phenotypic and Genotypic Characterization of RP1L1-Associated Retinopathy
PMID: 40172514
Gene: RP1L1
HGNC: 15946
Disease: occult macular dystrophy
MONDO: 0013316
InheritancePattern: autosomal dominant
Prevalence: The prevalence of occult macular dystrophy is "significantly less than one in 10,000 or 100,000 (https://www.reviewofoptometry.com/article/the-best-is-yet-to-come-feb).
Penetrance: The disease is known to be incompletely penetrant in family members carrying the heterozygous p.Arg45Trp variant (PMID: 20826268).
A novel mutation at the N-terminal domain of the TIMP3 gene in Sorsby fundus dystrophy
PMID: 23023527
Gene: TIMP3
HGNC: 11822
Disease: Sorsby fundus dystrophy (SFD), also known as Sorsby's fundus dystrophy, Sorsby pseudoinflammatory fundus dystrophy, or hemorrhagic macular dystrophy
MONDO: 0007640
InheritancePattern: Autosomal Dominant
Prevalence: Estimated at 1 in 220,000 (PMID: 28847738)
Penetrance: Fully penetrant, onset between the third and sixth decades of life
A novel TIMP3 mutation associated with a retinitis pigmentosa-like phenotype
PMID: 32715858
Gene: TIMP3
HGNC: 11822
Disease: Sorsby fundus dystrophy (SFD), also known as Sorsby's fundus dystrophy, Sorsby pseudoinflammatory fundus dystrophy, or hemorrhagic macular dystrophy
MONDO: 0007640
InheritancePattern: Autosomal Dominant
Prevalence: Estimated at 1 in 220,000 (PMID: 28847738)
Penetrance: Fully penetrant, onset between the third and sixth decades of life
In this study, we describe a father and son
FamilyLabel: DeBenedictis_2020_Family_1
Family#PresentingHPOs: HP:0000662 (Nyctalopia), HP:0000518 (Cataract), HP:0000964 (Eczema), HP:0007663 (Reduced visual acuity), HP:0011510 (Drusen), HP:0007703 (Abnormality of retinal pigmentation), HP:0007894 (Hypopigmentation of the fundus)
Family#PresentingHPOFreeText: Onset in 5th decade of life, initial diagnosis not with SFD but with retinitis pigmentosa.
FamilyNotHPOs: N/A
FamilyNotHPOFreeText: Features of syndromic retinal dystrophy
CountryOrigin: N/A
Ethnicity: Proband has Dutch ancestry on maternal (affected) side and North Irish / English on paternal (unaffected) side.
Race: Caucasian
Family#PreviousTesting: Limited (non genome-wide) genetic testing confirming absence of pathogenic variants in 13 different genes; RHO, PRPH2/RDS, RP1, IMPDH1, PRPF31, PRPF, PRPF8, NR2E3, SNRNP200, TOPORS, KLHL7, RPGR, and RP2.
Family#Method1: Limited genetic testing for 13 candidate genes
Family#Method2: N/A
Family#GenotypingMethod: next-generation sequencing analysis of an 856-gene retinal dystrophy panel
Affected: 2
Unaffected: 0
Segregations: There was 1 segregation reported, while consanguinity was not mentioned. The pedigree was not depicted.
PublishedLOD: N/A
eLOD: N/A
AddSegregationInfo: N/A
ProbandLabel: DiBenedetto_Patient_1
Variant: NM_000362.5(TIMP3):c.410A>G (p.Tyr137Cys)
CAID: CA411539826
gnomAD: The variant is not found in gnomAD.
FamilyAddInfo: The proband has a number of family members diagnosed with retinitis pigmentosa (son, sister, brother, mother, maternal grandmother, and maternal great-uncle ). The pattern was consistent with autosomal dominant inheritance. His sister underwent treatment for choroidal neovascularization at age 73.
FamilyPMIDs: N/A
Retinal Development and Pathophysiology in Kcnj13 Knockout Mice
PMID: 35096838
Gene: KCNJ13
HGNC: 6259
Disease: Leber congenital amaurosis 16
MONDO: 0013613
InheritancePattern: autosomal recessive
Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns (PMID: 10951519), while the proportion of Leber congenital amaurosis caused by KCNJ13 variants is unknown.
Penetrance: Known disease-causing alleles appear to be completely penetrant.
affected members
Case#: Huang_1995_Family_#3397_Patient_AR76, male, age and ethnic origin note mentioned
CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000662 (Nyctalopia), HP:0007994 (Peripheral visual field loss), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007737 (Bone spicule pigmentation of the retina), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude), HP:0007984 (Electronegative electroretinogram)
CaseHPOFreeText: The proband and his affected family members have been diagnosed with autosomal retinitis pigmentosa.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Sanger sequencing of PDE6A has been performed in the patient and her affected family members.
CaseMethod1: SSCP
CaseMethod2: Sanger sequencing of PDE6A
CaseGenotypingMethod: The patient and his affected sibling were subjected to SSCP of PDE6A PCR products followed by Sanger sequencing to identify the variant.
Variant: The proband harbors the NM_000440.3(PDE6A):c.1032C>A (p.Ser344Arg) and NM_000440.3(PDE6A):c.1683G>A (p.Trp561Ter) variants in the compound heterozygous state.
ClinVar: 13111, 13112
gnomAD: NM_000440.3(PDE6A):c.1032C>A (p.Ser344Arg) was not found in gnomAD v2.1.1, while NM_000440.3(PDE6A):c.1683G>A (p.Trp561Ter) was found at a frequency of 0.000008792 (1/113736) in the European non-Finnish population. https://gnomad.broadinstitute.org/variant/5-149274791-C-T
VariantEvidence: NM_000440.3(PDE6A):c.1032C>A (p.Ser344Arg) is a missense variant in exon 7 of 22 total, and does not have evidence of a functional effect on the protein product. NM_000440.3(PDE6A):c.1683G>A (p.Trp561Ter) is a nonsense variant in exon 13 of 22 total, and is predicted to trigger NMD or to at least disrupt the C-terminal 35% of the protein product.
CaseAddInfo: The proband is from a family with an affected sibling and unaffected parents.
CasePMIDs: N/A
TCD-G, an Irish family with autosomal dominant retinitis pigmentosa (adRP), to an 8.8 Mb region on 1p31. Of 50 known genes in the region, 11 candidates, including RPE65 and PDE4B, were sequenced using di-deoxy capillary electrophoresis. Simultaneously, a subset of family members was analyzed using Agilent SureSelect All Exome capture, followed by sequencing on an Illumina GAIIx platform. Candidate gene and exome sequencing resulted in the identification of an Asp477Gly mutation in exon 13 of the RPE65 gene tracking with the disease in TCD-G
FamilyLabel: Bowne_2011_Family_TCD-G
Family#PresentingHPOs: HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0007994 (Peripheral visual field loss), HP:0000533 (Chorioretinal atrophy), HP:0000546 (Retinal degeneration)
Family#PresentingHPOFreeText: Onset was in the 2nd to 5th decade of life, typically with impaired dark adaptation. Genotype-positive members of the family exhibited a wide range of phenotypes.
FamilyNotHPOs: HP:0003593 (Infantile onset), HP:0011463 (Childhood onset)
CountryOrigin: Ireland
Ethnicity: Not mentioned
Race: Not mentioned
Family#PreviousTesting: SNP-based linkage analysis was performed on all family members, mapping the phenotype of autosomal dominant retinitis pigmentosa to an 8.8-Mb genomic region located at chr1 p31. Whole exome sequencing of 3 affected an 1 unaffected family members then identified candidate variants of interest.
Family#Method1: SNP-based linkage analysis and whole exome sequencing of a subset of family members
Family#Method2: Candidate gene sequencing
Family#GenotypingMethod: Sanger sequencing of 11 candidate genes among the 50 known genes from the mapped region, including RPE65 and PDE4B.
Affected: 20
Unaffected: N/A
Segregations: 21 segregations were reported. 4 genotype-positive individuals were unaffected (reflecting reduced penetrance), with one of them having an affected child. The pedigree can be found in Figure 1a. Consanguinity of the family was not mentioned.
PublishedLOD: 3.6
eLOD: 6.32
AddSegregationInfo: 4 genotype-positive individuals were unaffected, with one of them having an affected child. Another non-genotyped but unaffected individual had an affected child as well. In combination with the 20 genotype-positive and phenotype-positive individuals, this reflects incomplete penetrance of approximately 80%.
ProbandLabel: Bowne_2011_Family_TCD-G_Patient_53
Variant: Affected individuals harbor the NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant in one allele of RPE65.
ClinVar: 750796
gnomAD: The NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant was not found in gnomAD.
FamilyAddInfo: N/A
FamilyPMIDs: PMID: 20861475
Ten of our patients with CSNB2 showed no mutation in CACNA1F. To identify the disease-causing mutations, we used a candidate-gene approach. CABP4, a member of the calcium-binding protein (CABP) family, is located in photoreceptor synaptic terminals and is directly associated with the C-terminal domain of the Cav1.4 alpha . Mice lacking either Cabp4 or Cav1.4 alpha display a CSNB2-like phenotype. Here, we report for the first time that mutations in CABP4 lead to autosomal recessive CSNB. Our studies revealed homozygous and compound heterozygous mutations in two families
Case#: Zeitz_2006_Family_A_II-5, male, onset in early childhood, family ancestry reported as Swiss
CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000639 (Nystagmus), HP:0007663 (Reduced visual acuity), HP:0000613 (Photophobia)
CaseHPOFreeText: The proband and his sibling have diagnosis of congenital stationary night blindness, in the absence of family history of the disease. BCVA was 20/100 at age 15 years. Disease course was stationary for 30 years but later included a decrease in visual acuity and development of moderate photophobia.
CaseNotHPOs: HP:0000662 (Nyctalopia)
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous genotyping was limited to Sanger sequencing of PCR products from the CACNA1F gene. The authors also implied that similarly screening was performed all other known genes associated CSNB, which at the time included RHO, GNAT1, PDE6B, GRK1, SAG, NYX, and GRM6.
CaseMethod1: Sanger sequencing of CABP4
CaseMethod2: N/A
CaseGenotypingMethod: Genotyping was limited to Sanger sequencing of PCR products from the CACNA1F and CABP4 genes, with possible sequencing of other known CSNB-associated genes RHO, GNAT1, PDE6B, GRK1, SAG, NYX, and GRM6.
Variant: The individual harbors the NM_145200.3(CABP4):c.800_801delAG variant in the homozygous state.
ClinVar ID: 1952
gnomAD: The variant is found in gnomAD version 4.1.1 at a frequency of 0.00007043 in the European (non-Finnish) population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/11-67226099-CAG-C?dataset=gnomad_r2_1
VariantEvidence: NM_145200.3(CABP4):c.800_801delAG is a frameshift variant within exon 6 of 6 that is predicted not to trigger nonsense-mediated decay but rather to disrupt the C-terminal 9 amino acids (3%) of the protein product and to extend the remaining protein by 91 additional amino acids. Analysis of patient mRNA indicates that splicing occurs normally but that expression at the mRNA level is decreased by more than 50% relative to the unaffected family member control.
CaseAddInfo: The proband's family is reportedly non-consanguineous, and includes a similarly affected brother who is also homozygous for the variant, as well as unaffected parents and 4 unaffected siblings who are heterozygous or lacking the variant (Figure 2A). Family history was negative for CSNB.
CasePMIDs: N/A
SFD family
FamilyLabel: Jacobson_1995_Family_1
Family#PresentingHPOs: HP:0000662 (Nyctalopia), HP:0011510 (Drusen), HP:0200056 (Macular scar), HP:0000608 (Macular degeneration), HP:0000603 (Central scotoma), HP:0025243 (Subretinal hemorrhage)
FamilyHPOFreeText: Onset in the 4th or early 5th decade of life with drusen appearing first and progression to macular scarring and degeneration.
FamilyNotHPOs: N/A
FamilyNotHPOFreeText: N/A
CountryOrigin: United States (mentioned in PMID:8981947)
Family#PreviousTesting: SSCP using PCR-amplified exon 5 from TIMP3, followed by Sanger sequencing of the exon 5 PCR product.
Family#GenotypingMethod: PCR amplification of exon 5 in samples from each family member, followed by enzyme digestion with the Bbv1 restriction endonuclease.
Affected: 6
Unaffected: 2
Segregations: 5
PublishedLOD: N/A
eLOD: 1.5
AddSegregationInfo: N/A
ProbandLabel: Jacobson_1995_Family_1_Patient_III-5
Variant: Patients harbor the NM_000362.5(TIMP3):c.568G>T (p.Gly190Cys) missense variant.
CAID: CA411540415
gnomAD: Variant is absent from gnomAD.
FamilyAddInfo: N/A
FamilyPMIDs: N/A
Clinical genomics can facilitate countrywide estimation of autosomal recessive disease burden
PMID: 27124789
Gene: PDE6C
HGNC: 8787
Disease: cone dystrophy 4
MONDO: 0013129
InheritancePattern: recessive
Prevalence: cone dystrophy in general is estimated to have a prevalence of 1 in 40,000 (PMID: 30578485).
Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.
Iris hyperpigmentation in a Chinese family with ocular albinism and the GPR143 mutation
PMID: 19610097
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
Mutation spectrum and clinical investigation ofachromatopsia patients with mutations in the GNAT2 gene
PMID: 31058429
GeneName: GNAT2
HGNC: 4394
Disease: achromatopsia 4
MonDO ID: MONDO_0013465
Inheritance: autosomal recessive
As illustrated for family R5, affected males have a 238-bp fragment, unaffected males have a 262-bp fragment and carrier females have both fragments. Affected individuals from 5 other families also have the shorter 238-bp fragment.
Case#: Bech-Hansen_2000_Family_R5_proband, male, age and race not mentioned, national origin in the United States
CasePresentingHPOs: HP:0030640 (Complete congenital stationary night blindness), HP:0030469 (Abnormal dark-adapted electroretinogram)
CaseHPOFreeText: At least one of two ERG abnormalities were observed in each affected family member; absence of rod psychophysical dark adaptation and/or absence of rod ERG with low-intensity blue flash.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Linkage analysis was originally performed in PMID: 2574143 using 17 X-chromosomal restriction fragment length polymorphism markers.
CaseMethod1: Agarose gel electrophoresis of the relevant PCR product to monitor segregation in the proband and family members
CaseMethod2: Sanger sequencing of PCR amplified exons from NYX
CaseGenotypingMethod: Linkage analysis was initially performed in PMID: 2574143 using 17 X-chromosomal restriction endonuclease-based markers. The proband and family members were then subjected to gel electrophoresis analysis of PCR products and Sanger sequencing to identify the variant.
Variant: The proband harbors the NM_001378477.3(NYX):c.70_93del (p.Arg24_Ala31del) variant on the X chromosome.
ClinVar: 99841
gnomAD: NM_001378477.3(NYX):c.70_93del (p.Arg24_Ala31del) has a maximum allele frequency of 0.0001018 (1/9823, with no males or homozygous females) in the European non-Finnish population https://gnomad.broadinstitute.org/variant/X-41332781-GGCCTGCGCCCGCGCTTGTCCCGCC-G
VariantEvidence: This in-frame deletion variant does not have experimental evidence of impact on the protein product, but is a recurrent variant observed in multiple apparently unrelated families (PMID: 2574143 and Figure 5 from this paper).
CaseAddInfo: Family phenotypes were described in PMID: 2574143.
CasePMIDs: PMID: 2574143
We found seven families from the US to share the same in-phase 24-nt deletion, which we predict results in the loss of the 8 amino acids RACPAACA from the N-terminal cysteine cluster of NYX (Fig. 3a). A genotype analysis of the X chromosomes with this deletion suggests that these families share a common founder mutation (Table 1).
FamilyLabel: Bech-Hansen_2000_Family_R5
Family#PresentingHPOs: HP:0030640 (Complete congenital stationary night blindness), HP:0030469 (Abnormal dark-adapted electroretinogram)
Family#PresentingHPOFreeText: At least one of two ERG abnormalities were observed in each affected family member; absence of rod psychophysical dark adaptation and/or absence of rod ERG with low-intensity blue flash
FamilyNotHPOs: N/A
CountryOrigin: The United States
Ethnicity: Not mentioned
Race: Not mentioned
Family#PreviousTesting: Linkage analysis was originally performed in PMID: 2574143 using 17 X-chromosomal restriction fragment length polymorphism markers.
Family#Method1: Agarose gel electrophoresis of the relevant PCR product to monitor segregation in family members
Family#Method2: Sanger sequencing of PCR amplified exons from NYX
Family#GenotypingMethod: Linkage analysis was initially performed in PMID: 2574143 using 17 X-chromosomal restriction endonuclease-based markers. Family members were then subjected to gel electrophoresis analysis of PCR products and Sanger sequencing to identify the variant.
Affected: 4
Unaffected: 5
Segregations: 6 segregations (all consistent) among genotyped individuals are shown in this paper (pedigree in Fig. 3).
PublishedLOD: 7.35 (in PMID: 2574143, combined from 7 families)
eLOD: 1.8
AddSegregationInfo: N/A
ProbandLabel: Bech-Hansen_2000_Family_R5_proband
Variant: Affected male family members harbor the NM_001378477.3(NYX):c.70_93del (p.Arg24_Ala31del) variant on the X chromosome.
ClinVar: 99841
gnomAD: NM_001378477.3(NYX):c.70_93del (p.Arg24_Ala31del) has a maximum allele frequency of 0.0001018 (1/9823, with no males or homozygous females) in the European non-Finnish population https://gnomad.broadinstitute.org/variant/X-41332781-GGCCTGCGCCCGCGCTTGTCCCGCC-G
FamilyAddInfo: Family phenotypes were described in PMID: 2574143.
FamilyPMIDs: PMID: 2574143
Ocular albinism: evidence for a defect in an intracellular signal transduction system
PMID: 10471510
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
splice site mutation, G→C, was detected in family X03 at position +1 in intron 2.
Case#: Allen_2003_Familly_X03_Proband, male, age not mentioned, British national origin
CasePresentingHPOs: HP:0007642 (Congenital stationary night blindness), HP:0007663 (Reduced visual acuity), HP:0031624 (Moderate myopia), HP:0007984 (Electronegative electroretinogram)
CaseHPOFreeText: ERG with absent scotopic oscillatory potential, subnormal ON response
CaseNotHPOs: N/A
CaseNotHPOFreeText: Normal OFF response
CasePreviousTesting: N/A
CaseMethod1: Sanger sequencing of PCR-amplified exons from NYX and CACNA1F
CaseMethod2: Haplotype analysis using microsatellite markers surrounding the NYX locus
CaseGenotypingMethod: The proband and family members were subjected to Sanger sequencing of NYX to identify the variant, followed by microsatellite-based haplotype analysis of families sharing the same variant.
Variant: The proband harbors the NM_022567.2(NYX):c.37+1G>C (p.=) variant on the X chromosome.
CAID: CA412988630
gnomAD: NM_022567.2(NYX):c.37+1G>C (p.=) was not found in gnomAD.
VariantEvidence: This splice site variant disrupts a canonical splice site between the two coding exons (exon 2 and exon 3), and is therefore predicted to disrupt the protein product.
CaseAddInfo: N/A
CasePMIDs: N/A
an in-frame 15 bp deletion in exon 3a in two families (X04 and X06)
Case#: Allen_2003_Familly_X04_Proband, male, age not mentioned, British national origin
CasePresentingHPOs: HP:0007642 (Congenital stationary night blindness), HP:0007663 (Reduced visual acuity), HP:0031624 (Moderate myopia), HP:0007984 (Electronegative electroretinogram)
CaseHPOFreeText: ERG with absent scotopic oscillatory potential, subnormal ON response
CaseNotHPOs: N/A
CaseNotHPOFreeText: Normal OFF response
CasePreviousTesting: N/A
CaseMethod1: Sanger sequencing of PCR-amplified exons from NYX and CACNA1F
CaseMethod2: Haplotype analysis using microsatellite markers surrounding the NYX locus
CaseGenotypingMethod: The proband and family members were subjected to Sanger sequencing of NYX to identify the variant, followed by microsatellite-based haplotype analysis of families sharing the same variant.
Variant: The proband harbors the NM_022567.2 (NYX):c.339_353del (p.Glu114_Ala118del) variant on the X chromosome.
CAID: CA2573050968
gnomAD: NM_022567.2 (NYX):c.339_353del (p.Glu114_Ala118del) was not found in gnomAD.
VariantEvidence: NM_022567.2:c.339_353del is an in-frame deletion variant that removes 5 amino acids from the center of the polypeptide sequence. It is a recurrent variant reported here in multiple apparently unrelated British families (X04 and X06).
CaseAddInfo: N/A
CasePMIDs: N/A
Australian Cattle Dogs with Neuronal Ceroid Lipofuscinosis are Homozygous for a CLN5 Nonsense Mutation Previously Identified in Border Collies
PMID: 27203721
Gene: CLN5
HGNC: 2076
Disease: Ceroid lipofuscinosis, neuronal, 5 (also known as Finnish variant late infantile neuronal ceroid lipofuscinosis, neuronal ceroid lipofuscinosis late infantile Finnish variant, or Finnish vLINCL)
MONDO: 0009745
InheritancePattern: Autosomal Recessive
Prevalence: Unknown, but part of a larger group of NCL disorders with a collective prevalence between 1 in 12,500 (PMID:9662406) and 1 in 100,000 (PMID:23374165)
Penetrance: Fully penetrant, with onset often in the late infantile period but in some cases during early adulthood or even as late as in the 6th decade of life
The protein lysate of mIMCD3-Ift140−/− cells validated the absence of IFT140 protein in these cells (Fig. 3a). Upon transfection with wild-type or p.Tyr923Asp mutant IFT140, a partial rescue of the IFT140 protein level was detected. There was no IFT140 signal detected in the protein lysate of mIMCD3-Ift140−/− transfected with p.Tyr332Valfs*18. To exclude that the observed ciliary tip accumulation of IFT88 in patient-derived URECs was due to other variants, we assessed the ability of patient mutant IFT140 constructs to rescue ciliogenesis and determined the localization of IFT88. Ciliogenesis was restored in 11% of the analyzed cells upon rescue with wild-type IFT140. Both mutants, p.Tyr923Asp and p.Tyr332Valfs*18, rescued ciliogenesis in 6% of the cells (Fig. 3b). Defects in retrograde IFT were visualized by ciliary tip accumulation of IFT-B protein IFT88. Cilia rescued with the p.Tyr923Asp mutant IFT140 showed IFT88 ciliary tip accumulation in 50%, which is significantly more than seen in ciliated cells rescued with wild-type IFT140 (23% tip accumulation). A similar phenotype was seen in ciliated cells transfected with p.Tyr332Valfs*18 IFT140 (56% tip accumulation).
ExperimentName: IFT140 variant rescue in Ift140 knockout cells
RescueCellLine: Mouse Inner Medullary Collecting Duct 3 (mIMCD3) cells
RescueCellEFO: EFO:0002887 (mouse cell line), EFO:0001643 (kidney-derived cell line)
GeneAlteration: The cell line was subjected to CRISPR-based knockout of endogenous IFT140 (targeting exon 8).
RescueCellPhenotype: Ift140 knockout cells exhibited a complete inability to form cilia relative to the control rescued by overexpression of wild-type Ift140 (Figure 3b) and aberrant accumulation of the IFT-B protein IFT88 at the ciliary tip (Figure 3d).
RescueMethod: Transient transfection and over-expression of wild-type or variant IFT140 was used to rescue the cell phenotypes.
RescueEvidence: Wild-type IFT140 restored ciliogenesis in 11% of cells, while either variant restored ciliogenesis to 6%, despite the surprising continued absence of the frameshift variant at the protein level (Figure 3b). Wild-type IFT140 reduced the proportion of cells exhibiting IFT88 accumulation at the ciliary tip to 23%, while either variant partially reduced IFT88 localization to the ciliary tip to 50% or 56% (Figure 3d).
RescueCellVariant: The variants used for the rescue experiment were NM_014714.3(IFT140):c.992_993dup (p.Tyr332Valfs*18) (cannot be registered manually) and NM_014714.3:c.2767T>G (p.Tyr923Asp) (CA394227092).
Proteoglycan IMPG2 Shapes the Interphotoreceptor Matrix and Modulates Vision
PMID: 32265257
Gene: IMPG1
HGNC: 6055
Disease: vitelliform macular dystrophy 4
MONDO: 0014508
InheritancePattern: semi-dominant
Prevalence: Vitelliform macular dystrophy in general is estimated to have a prevalence of 1 in 5,500 (PMID: 27120116).
Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete, while heterozygous carriers of deleterious variants show incomplete penetrance and variable expressivity.
The ocular albinism type 1 protein, an intracellular G protein-coupled receptor, regulates melanosome transport in pigment cells
PMID: 18697795
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
NYX (Nyctalopin on Chromosome X), the Gene Mutated in Congenital Stationary Night Blindness, Encodes a Cell Surface Protein
PMID: 14507859
Gene: NYX
HGNC: 8082
Disease: Congenital stationary night blindness 1A
MONDO: 0010690
InheritancePattern: X-linked recessive
Prevalence: Congenital stationary night blindness has an estimated prevalence between 1 in 6,000 (PMID: 31427709) and 1 in 300,000 (PMID: 3487908). However, the prevalence of congenital stationary night blindness 1A specifically is unknown.
Penetrance: Penetrance is thought to be complete.
Autosomal dominant pattern dystrophy of the retina associated with a 4-base pair insertion at codon 140 in the peripherin/RDS gene
PMID: 7710395
Gene: PRPH2
HGNC: 9942
Disease: retinitis pigmentosa 7
MONDO: 0011974
InheritancePattern: semi-dominant
Prevalence: The incidence of PRPH2-related cases among inherited retinal dystrophies is reported to range from 3.5% in North America to 10.3% in France (PMID: 36010202).
Penetrance: The penetrance among biallelic cases appears to be complete, while the monoallelic cases exhibit incomplete penetrance (PMID: 36609934).
Interaction between G-coupled Protein Receptor 143 and tyrosinase: Implications for understanding Ocular Albinism Type-1
PMID: 27720922
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
this gene
Case#: Mykykyn_2002_Proband_D, gender not specified, age not described, family origin reported as from Turkish
CasePresentingHPOs: N/A
CaseHPOFreeText: The proband has been previously diagnosed with Bardet-Biedl syndrome based on at least three of the following features; obesity, polydactyly, renal anomalies, retinopathy, hypogonadism, and/or mental retardation.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: The proband and their affected and unaffected family members were subjected to mapping of the disease-associated locus to chromosome 11, followed by PCR- and Sanger sequencing-based genotyping of chromosome 11 markers.
CaseMethod1: linkage mapping
CaseMethod2: Sanger sequencing of BBS1
CaseGenotypingMethod: The proband and their affected and unaffected family members were subjected to linkage mapping of the disease-associated locus to chromosome 11, followed by PCR- and Sanger sequencing-based genotyping of chromosome 11 markers. Sanger sequencing of BBS1 was subsequently used to identify the variant.
Variant: The proband harbors the NM_024649.5(BBS1):c.851del (p.Tyr284fs) variant in the homozygous state.
ClinVar ID: 12146
gnomAD: The variant is found in gnomAD v2.1.1 at a frequency of 0.00001758 (2 alleles out of 113768 total alleles, with 0 homozygotes) in the European non-Finnish population https://gnomad.broadinstitute.org/variant/11-66290946-TA-T?dataset=gnomad_r2_1
VariantEvidence: NM_024649.5(BBS1):c.851del (p.Tyr284fs) is a frameshift variant in exon 10 of 17 that is predicted to trigger nonsense mediated decay or to at least truncate the C-terminal 52% of the protein product.
CaseAddInfo: The proband's family is described as consanguineous.
CasePMIDs: N/A
Gene Therapy in a Large Animal Model of PDE6A-Retinitis Pigmentosa
PMID: 28676737
Gene: PDE6A
HGNC: 8785
Disease: retinitis pigmentosa 43
MONDO: MONDO:0013437
InheritancePattern: autosomal recessive
Prevalence: The overall prevalence of retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of retinitis pigmentosa with a recessive mode of inheritance is estimated to be 65-85% (between 1 in 3,500 and 1 in 6,200). Retinitis pigmentosa 43 is considered to be make up 2-5% of these cases, with an overall prevalence estimated between 1 in 70,000 and 1 in 310,000.
Penetrance: Known disease-causing alleles appear to be completely penetrant.
Eighteen individuals of family 1 underwent ophthalmological examination (Figure 1a)
FamilyLabel: Naessens_2019_Family_1
FamilyPresentingHPOs: HP:0011510 (Drusen)
FamilyHPOFreeText: Relatively late onset of phenotypes between ages 49 and 74. Drusen / deposits were universal except for 3 individuals between the ages of 37 and 47.
**FamilyNotHPOs: N/A
FamilyNotHPOFreeText: Pulmonary involvement
CountryOrigin: Belgium
Family#PreviousTesting: Yes, SSCP and Sanger sequencing were both previously performed (PMID:10873973), but results were negative (no TIMP3 variant found).
Family#Method1: SSCP of all five exons, plus the promoter and 3'UTR of TIMP3
Family#Method2: Sanger sequencing of PCR-amplified exon 5 of TIMP3
Family#GenotypingMethod: PCR amplification of all 5 coding exons of TIMP3, followed by Sanger sequencing
Affected: 18
Unaffected: 29
Segregations: 23
PublishedLOD: N/A
eLOD: 6.9
AddSegregationInfo: N/A
ProbandLabel: Naessens_2019_Family_1_patient_IV:31
Variant: The variant is NM_000362.5(TIMP3):c.113C>G (p.Ser38Cys), a missense variant predicted to introduce a new cysteine-encoding codon into exon 1.
ClinVar: 843268
gnomAD: Variant is absent from gnomAD.
FamilyAddInfo: Family was previously genotyped in PMID:10873973, but SSCP analysis of all 5 exons and Sanger sequencing of exon 5 were not sufficient at that time to detect the variant in exon 1.
FamilyPMIDs: PMID:10873973
five probands from family 1 (IV:31, IV:56, IV:59, V:30, and V:33)
Case: Naessens_2019_Family_1_Patient_IV:31, female, age of onset 51 years old, country of origin Belgium
DiseaseAssertion: Sorsby's fundus dystrophy
FamilyInfo: Familial variant appears to come from a founder mutation shared by other families in Belgium and northern France with a distant common ancestor.
CasePresentingHPOs: HP:0011510 (Drusen), HP:0000613 (Photophobia), HP:0000572 (Visual loss)
CaseHPOFreeText: Relatively late onset of phenotypes (at age 51, presenting with photophobia). Drusen was described as widespread around the vascular arcades.
CaseNOTHPOs: N/A
CaseNOTHPOFreeText: Pulmonary involvement
CasePreviousTesting: Yes, SSCP and Sanger sequencing were both previously performed (PMID:10873973), but results were negative (no TIMP3 variant found).
CaseMethod1: SSCP of all five exons, plus the promoter and 3'UTR of TIMP3
CaseMethod2: Sanger sequencing of PCR-amplified exon 5 of TIMP3
GenotypingMethod: PCR amplification of all 5 coding exons of TIMP3, followed by Sanger sequencing
PreviouslyPublished: PMID:10873973
SupplementalData: Supplementary Table S3 from this paper (PMID: 30668888) provides some of the proband phenotype details.
Variant: The variant is NM_000362.5(TIMP3):c.113C>G (p.Ser38Cys), a missense variant predicted to introduce a new cysteine-encoding codon into exon 1.
ClinVar: 843268
gnomAD: Variant is absent from gnomAD.
VariantEvidence: Variant adds a Cys residue to TIMP3 and is predicted to disrupt tertiary structure. Patient fibroblasts reveal no change in expression of the variant at the mRNA level, no dimerization of the variant under non-reducing conditions, and no defect in its localization to the ECM. Variant showed a minor increase in glycosylation. An in vitro transcription and translation study found that the variant forms an aberrant intramolecular disulfide bond between the introduced Ser38Cys residue and Cys36 of TIMP3 (Figure 7). Aberrant intramolecular disulfide bonding caused by this variant would be consistent gain-of-function and an autosomal dominant mechanism of inheritance.
Retinal dystrophy of Swedish briard/briard-beagle dogs is due to a 4-bp deletion in RPE65
PMID: 10191083
Gene: RPE65
HGNC: 10294
Disease: Leber congenital amaurosis 2
MONDO: 0008765
InheritancePattern: Autosomal Recessive
Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by RPE65 variants is between 1% and 16.7%. Thus, the prevalence of Leber congenital amaurosis 2 is between 1 in 200,000 and 1 in 10,000,000.
Penetrance: Fully penetrant, with onset typically by 1 year of age
Nyctalopin is expressed postsynaptically in both synaptic layers of the retina.
Selection A - Gene is expressed in tissues relevant to disease:
ExperimentName: Nyx localization to the post-synaptic side of both synaptic layers of the zebrafish retina
TissueExpression: UBERON:0001790 (Outer plexiform layer of retina), UBERON:0001795 (Inner plexiform layer of retina
ExpressionEvidence: Nyx was detected by antibody staining of zebrafish retinal sections and was found to localize strongly to both synaptic layers (the outer plexiform layer and inner plexiform layer) but not the outer nuclear layer or inner nuclear layer (Fig. 5A). Lack of co-localization between Nyx and either SV2 or PSD-95 (two presynaptic markers) confirmed that Nyx is specifically post-synaptically localized (Figs. 5C, 6A). This was further confirmed by the detection of Nyx-labeled second-order neuron dendrites invaginating into presynaptic cone pedicles (Figs. 6B and 6C). This data is highly compatible with the findings of a separate mouse experiment (PMID: 17881478) showing that Nyx transgene expression in the dendritic tips of retinal depolarizing bipolar cells rescues the phenotype of Nyx-deficient mice.