100
Case#: 100, male, 15 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 3.2%
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.6551A>C
LegacyVariant:
ClinVar: No
CAID: CA414907026
gnomAD:
29
Case#: 29, male, 21 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 2.3%
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.337C>T
LegacyVariant:
ClinVar: No
CAID: CA414919977
gnomAD:
74
Case#: 74, male, 60 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 11%
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:
87
Case#: 87, male, 11 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 3.9%
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.6406G>A
LegacyVariant:
ClinVar: No
CAID: CA414899430
gnomAD:
120
Case#: 120, male, 51 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.5220-2A>G
LegacyVariant:
ClinVar: No
CAID: CA414911437
gnomAD:
60
Case#: 60, male, 19 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
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.2029T>C
LegacyVariant:
ClinVar: 10244
CAID: CA255136
gnomAD:
104
Case#: 104, male, 13 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.6683G>A
LegacyVariant:
ClinVar: 10098
CAID: CA255016
gnomAD:
138
Case#: 138, male, 9 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.dup exons23_25
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
79
Case#: 79, male, 8 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.5594A>G
LegacyVariant:
ClinVar: No
CAID: CA414908275
gnomAD:
2
Case#: 2, male, 11 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.98G>A
LegacyVariant:
ClinVar: No
CAID: CA414920533
gnomAD:
182
Case#: 182, male, 25 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
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 exons15_26
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
12
Case#: 12, male, 7 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.1798G>T
LegacyVariant:
ClinVar: No
CAID: CA414911019
gnomAD:
9
Case#: 9, male, 19 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
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.1285C>T
LegacyVariant:
ClinVar: No
CAID: CA414915370
gnomAD:
114
Case#: 114, male, 16 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 3%
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.601+1G>C
LegacyVariant:
ClinVar: No
CAID: CA414919361
gnomAD:
5
Case#: 5, male, 9 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.741G>A
LegacyVariant:
ClinVar: No
CAID: CA414919022
gnomAD:
64
Case#: 64, male, 6 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.2158G>C
LegacyVariant:
ClinVar: No
CAID: CA414903786
gnomAD:
23
Case#: 23, male, 21 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.6496C>T
LegacyVariant:
ClinVar: 10096
CAID: CA255013
gnomAD:
99
Case#: 99, male, 9 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.6544C>T
LegacyVariant:
ClinVar: 10321
CAID: CA255214
gnomAD:
92
Case#: 92, male, 61 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 4.2%
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.6440G>T
LegacyVariant:
ClinVar: No
CAID: CA414908004
gnomAD:
106
Case#: 106, male, 12 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.6683G>A
LegacyVariant:
ClinVar: 10098
CAID: CA255016
gnomAD:
54
Case#: 54, male, 9 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 17%
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:
016–2003
Case#: 016-2003
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.2129G>A
LegacyVariant:
ClinVar: No
CAID: CA414904142
gnomAD:
020–1011
Case#: 020-1011
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:
004–2017
Case#: 004-2017
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:
LegacyVariant:
ClinVar: No
CAID:
gnomAD:
091–2004
Case#: 091-2004
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.5281T>C
LegacyVariant:
ClinVar: No
CAID: CA414911024
gnomAD:
038–2025
Case#: 038-2025
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.514T>G
LegacyVariant:
ClinVar: No
CAID: CA414919550
gnomAD:
016–2005
Case#: 016-2005
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.3531_3533delA
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
004–2008
Case#: 004-2008
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.4379dupA
LegacyVariant:
ClinVar: No
CAID: CA645292749
gnomAD:
035–2021
Case#: 035-2021
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:
035–1005
Case#: 035-1005
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.1271þ1G>C
LegacyVariant:
ClinVar: No
CAID: CA414915615
gnomAD:
038–2011
Case#: 038-2011
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.5252A>G
LegacyVariant:
ClinVar: No
CAID: CA414911251
gnomAD:
020–2057
Case#: 020-2057
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:
LegacyVariant:
ClinVar: No
CAID:
gnomAD:
035–2019
Case#: 035-2019
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.923C>T
LegacyVariant:
ClinVar: No
CAID: CA255082
gnomAD:
035–2001
Case#: 035-2001
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:
071–2027
Case#: 071-2027
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.4184_4186delGGAinsCCTC
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
020–1016
Case#: 020-1016
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:
015–2006
Case#: 015-2006
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.343G>T
LegacyVariant:
ClinVar: No
CAID: CA414919965
gnomAD:
060–2001
Case#: 060-2001
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:
gnomAD:
066–2003
Case#: 066-2003
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.1649G>A
LegacyVariant:
ClinVar: No
CAID: CA255115
gnomAD:
010–1001
Case#: 010-1001
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.6742T>A
LegacyVariant:
ClinVar: No
CAID: CA414904758
gnomAD:
002–2002
Case#: 002-2002
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.2092T>C
LegacyVariant:
ClinVar: No
CAID: CA414908999
gnomAD:
038–2023
Case#: 038-2023
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.322_332þ8delGCTTCTGAGGGtgagtaaa
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
002–2006
Case#: 002-2006
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.4379delA
LegacyVariant:
ClinVar: No
CAID: CA255151
gnomAD:
001–2040
Case#: 001-2040
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.5630G>A
LegacyVariant:
ClinVar: No
CAID: CA414908131
gnomAD:
003–2001
Case#: 003-2001
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.493C>T
LegacyVariant:
ClinVar: No
CAID: CA255065
gnomAD:
Table 1
Case#: Cz12, 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.5953C>T (p.Arg1985Ter)
ClinVar: 10300 https://www.ncbi.nlm.nih.gov/clinvar/variation/10300/
CAID: CA255191
gnomAD: Not reported
Table 1
Case#: Cz31, Italy (Calabria)
DiseaseAssertion: Hemophilia A
FamilyInfo: Inherited
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:c.1324T>C (p.Tyr442His)
ClinVar: NA
CAID: CA414915029
gnomAD: Not reported
Table 2
Case#: Cz11, 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#: Cz26, Italy (Calabria)
DiseaseAssertion: Hemophilia A
FamilyInfo: Inherited
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVII:C 1.5%
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 1
Case#: Cz37, Italy (Calabria)
DiseaseAssertion: Hemophilia A
FamilyInfo: Inherited
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:c.4379dup (p.Asn1460LysfsTer2)
ClinVar: NA
CAID: CA645292749
gnomAD: MAF for p.Asn1460LysfsTer2 in the European (non-Finnish) population 0.00001245<br>https://gnomad.broadinstitute.org/variant/X-154157685-A-AT
c.1648C>T
Case#: 13
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 25/21% (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.1648C>T (p.Arg550Cys)
ClinVar: 10223 https://www.ncbi.nlm.nih.gov/clinvar/variation/10223/
CAID: CA255113
gnomAD: Not reported
c.5999–740T>C
Case#: 26
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 33%, 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.5999-740T>C
ClinVar: NA
CAID: CA1139532039
gnomAD: Not reported
c.1052G>A
Case#: 39
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C <1% (Severe 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_000133.3:c.1052G>A (p.Gly351Asp)
ClinVar: NA
CAID: CA414445595
gnomAD: Not reported
c.6046C>T
Case#: 27
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 4% (Moderate 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.6046C>T (p.Arg2016Trp)
ClinVar: 10304 https://www.ncbi.nlm.nih.gov/clinvar/variation/10304/
CAID: CA255197
gnomAD: Not reported
c.6750A>C
Case#: 35
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 24/32/19/17/35%, 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.6750A>C (p.Gln2250His)
ClinVar: NA
CAID: CA414904711
gnomAD: Not reported
c.5936G>A
Case#: 25
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 21/17%, 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.5936G>A (p.Gly1979Glu)
ClinVar: NA
CAID: CA414905839
gnomAD: Not reported
c.157G>A
Case#: 40
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C <1% (Severe 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_000133.3:c.157G>A (p.Glu53Lys)
ClinVar: NA
CAID: CA414435726
gnomAD: Not reported
c.1025C>T
Case#: 48
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C 3% (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_000133.3(F9):c.1025C>T (p.Thr342Met)
ClinVar: 10607 https://www.ncbi.nlm.nih.gov/clinvar/variation/10607/
CAID: CA255381
gnomAD: Not reported
c.6506G>A
Case#: 31
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 17/25%, Mild Phenotype, 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.6506G>A (p.Arg2169His)
ClinVar: 10315 https://www.ncbi.nlm.nih.gov/clinvar/variation/10315/
CAID: CA255208
gnomAD: Not reported
c.1010–842G>A
Case#: 7
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 34/30/35% (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.1010-842G>A
ClinVar: NA
CAID: CA337336857
gnomAD: MAF in Ashkenazi Jewish population 0.01105<br>https://gnomad.broadinstitute.org/variant/X-154195804-C-T
S23
Case#: S23, 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:
S5
Case#: S5, Iranian
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Mucosal bleeding
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: NM_000132.3:c.1010‐2A>G
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
S15
Case#: S15, 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:
S12
Case#: S12, Iranian
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Family history of HA
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: NM_000132.3:c.del exons8_9
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
S19
Case#: S19, Iranian
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Mucosal bleeding
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:
16-year-old boy
Case1: Male patient, 16-year-old, Tabriz Iran
DiseaseAssertion: Moderate Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0005261 (Joint hemorrhage), HP:0030137 (Prolonged bleeding following circumcision)
CasePreviousTesting: PCR-SSCP and PCR-CSGE was performed for all 26 exons with exon-intron boundaries of F8. Abnormal PCR product were directly sequenced.
Gene: F8
Variant: NM_000132.3(F8):c.4925A>G (p.Glu1642Gly)
ClinVar: NA
CAID: CA10568060
gnomAD: MAF for Glu1642Gly in the East Asian population 0.0001346 <br /> https://gnomad.broadinstitute.org/variant/X-154157140-T-C
The patient was born in 1944; at the age of 7 he underwent a tonsillectomy, bled excessively and required a blood transfusion. He had dental extractions when he was 14 and bled for a week afterwards. At 25 he had a birthmark removed from his left shoulder and again bled excessively. At that time two-stage FVIII:C assays were performed and he was diagnosed as having mild haemophilia A with a FVIII:C level of 19%. 3 years later (in 1972) he presented with a large haematoma of the buttock after minor trauma and a two-stage assay reported a FVIII:C level of 11%. Interestingly, his APTT was always normal. In 1977 he had sebaceous cysts removed under the cover of FVIII concentrate. He received further concentrate in 1982 following an injury to his left thigh and 6 weeks later developed hepatitis (in retrospect hepatitis C). He has not had any further bleeding problems. At a recent routine visit his baseline FVIII:C level was checked with our (now routine) one-stage assay and found to be normal. Subsequently on three blood samples taken on different days we obtained the assay results shown in Table I. On the second of these samples the factor VIII antigen was measured by Immunozym ELISA (Techniclone, Dorking) and found to be 82 iu/dl.
Case#: 77 year old male*
DiseaseAssertion:Hemophilia A, mild
FamilyInfo: Brother does not have hemophilia
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%, assay discrepancy present (OSA>CSA)
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The factor VIII coding region was amplified into six overlapping segments from traces of mRNA and from genomic DNA and subsequently sequenced
Gene: F8
Variant: NM_000132.3:c.5918A>T
LegacyVariant:
ClinVar:
CAID: CA414905984
gnomAD:
UQU-HA37
Case#: UQU-HA37, Male, 1-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: PTT 49.6, FVIII: 1 to <5% (Moderate), Disabled left knee
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.6430-1G>A
ClinVar: NA
CAID: CA414908097
gnomAD: Not reported
UQU-HB5
Case#: UQU-HB5, Male, 12-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Mild, PTT 47.3
CasePreviousTesting: Screened for all factor IX exons by capillary sequencing
Gene: F9
Variant: NM_000133.3(F9):c.316G>A (p.Gly106Ser)
ClinVar: 10579 https://www.ncbi.nlm.nih.gov/clinvar/variation/10579/
CAID: CA255329
gnomAD: MAF for Gly106Ser in the Other population 0.0001881<br>https://gnomad.broadinstitute.org/variant/X-138623273-G-A?dataset=gnomad_r2_1
Molecular Analysis of Factor VIII and Factor IX Genes in Hemophilia Patients: Identification of Novel Mutations and Molecular Dynamics Studies
PMID: 28270892
Gene: F8, F9
HGNCID: 3546, 3551
UQU-HA33
Case#: UQU-HA33, Male, 2-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: PTT 99.5, Disabled Right Knee, 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.760A>G (p.Asn254Asp)
ClinVar: NA
CAID: CA414918977
gnomAD: Not reported
UQU-HB6
Case#: UQU-HB6, Male, 11-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe, Disabled right knee, PTT 52.2
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-HA34
Case#: UQU-HA34, Male, 1-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: PTT 94, Disabled Left elbow, 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
Spectrum of F8 Genotype and Genetic Impact on Inhibitor Development in Patients with Hemophilia A from Multicenter Cohort Studies (J-HIS) in Japan
PMID: 33254277
Gene: F8
HGNCID: 3546
a woman diagnosed as a HA carrier
Case2: Female patient, blood group O
DiseaseAssertion: Severe Hemophilia A from de novo mutation
FamilyInfo: Family history of severe Hemophilia A, Son diagnosed with severe HA, Sibling has intron 22 inversion on F8 gene
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeRext: aPTT ratio 1.16 (within normal range ratio), FVIII:C 48% (low-normal)
CasePreviousTesting: Molecular analysis that excluded intron 22 inversion (HA carrier), tested for intron 22 inversion (confirmed negative), tested for intron 1 inversion (found negative), sequenced the whole coding region of the F8 gene(c.1753-1G>A mutation found)
Gene: F8
Variant: NM_000132.3:c.1753-1G>A
ClinVar: NA
CAID: CA414911340
gnomAD: Not reported
A1
Case#: A1
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 7, FVIII:AG = 25, 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.398A>G
LegacyVariant:
ClinVar: No
CAID: CA255061
gnomAD:
Usefulness of an in vitro cellular expression model for haemophilia A carrier diagnosis: illustration with five novel mutations in the F8 gene in women with isolated factor VIII:C deficiency
PMID: 25708597
Gene: F8
Disease: Hemophilia A
HGNC:3546
MONDO ID: MONDO:0010602
Role of chromogenic assays in haemophilia A and B diagnosis
PMID: 29808946
Gene: F8
HGNC: 3546
NoEvidence: This article discusses the role of chromogenic assays in hemophilia A; no case reports in this article
A genetic analysis of 23 Chinese patients with hemophilia B
PMID: 27109384
Gene: F9
HGNCID: 3551
Prediction of factor VIII inhibitor development in the SIPPET cohort by mutational analysis and factor VIII antigen measurement
PMID: 29399993
Gene: F8
HGNC: 3546
InsufficientEvidence: This article mentions variants however there are no specific case reports mentioned therefore, insufficient evidence
Homozygous and heterozygous retinal phenotypes in families harbouring IMPG2 mutations
PMID: 31264916
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.
homozygotes
Case#: Khan_2019_proband_1, male, age 8 years at time of report, national origin reported as Emirati
CasePresentingHPOs: HP:0000613 (Photophobia), HP:0000545 (Myopia), HP:0000577 (Exotropia), HP:0007663 (Reduced visual acuity), HP:0410280 (Pediatric onset), HP:0025158 (Hyperautofluorescent retinal lesion), HP:0030609 (Photoreceptor layer loss on macular OCT), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude)
CaseHPOFreeText: The patient has been diagnosed with childhood-onset rod-cone dystrophy with early macular involvement.
CaseNotHPOs: HP:0000639 (Nystagmus)
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous genotyping consisted of a retinal dystrophy gene panel.
CaseMethod1: retinal dystrophy gene panel
CaseMethod2: Sanger sequencing of the 19 exons of the IMPG2 gene
CaseGenotypingMethod: Genotyping consisted of a retinal dystrophy gene panel followed by Sanger sequencing of the 19 exons of the IMPG2 gene.
Variant: The patient harbors the NM_016247.4(IMPG2):c.189dup (p.Gln64fs) variant in the homozygous state.
ClinVar: 978976
gnomAD: The variant was found in gnomAD v2.1.1.
VariantEvidence: NM_016247.4(IMPG2):c.189dup (p.Gln64fs) is a frameshift variant in exon 2 of 19 that is predicted to trigger NMD or to at least truncate the C-terminal 95% of the protein product.
CaseAddInfo: The family is consanguineous, with the parents being first cousins and heterozygous carriers of the variant.
CasePMIDs: N/A
We demonstrate that in CLN5-depleted HeLa cells, the lysosomal sorting receptors sortilin and cation-independent mannose 6-phosphate receptor (CI-MPR) are degraded in lysosomes due to a defect in recruitment of the retromer (an endosome-to-Golgi compartment trafficking component).
ExperimentName: Defective lysosomal sorting receptor degradation in CLN5-depleted HeLa cells
NonPatientCell: HeLa cells (EFO:0001185)
GeneFunction: Lysosomal organization (GO:0007040)
GeneAlteration: CLN5 (or the CLN1 control) was depleted by transient transfection of small interfering RNA (siRNA) into HeLa cells, 48 hrs. before assays were performed.
FunctionalEvidence: CLN5-depleted cells have reduced immunofluorescent signal (Fig. 2K) and reduced expression (Fig. 3A) of two lysosomal sorting receptors; cation-independent mannose 6-phosphate receptor (CI-MPR) and sortilin (Fig. 2K). CLN5-depleted cells also have fragmented TGN46 signal (Fig. 2Q) and increased precursor and intermediate forms of the lysosomal cargo protein cathepsin D (Fig. 3C). These findings are consistent with CI-MPR and sortilin failing to correctly recycle to the Golgi and being degraded in lysosomes instead, possibly due to a defect in a complex called retromer, which returns membrane-associated proteins from the endosome to the Golgi or other cellular compartments. Endosomal signal for the retromer subunit Vps26 is also decreased (Fig. 4E), and both Vps26 and Vps35 are increasingly cytosolic rather than membrane-bound in CLN5-depleted cells (Fig. 6A). These defects are reversed by exogenously expressing CLN5 (Fig. 7B). Rab7 recruitment to the endosome is also defective in CLN5-depleted cells (Figs. 8B,8M). Considering that CLN5 interacts with Rab5 and Rab7 (Fig. 9A), it may serve as a scaffold recruiting Rab7 and the retromer complex to the endosomal membrane, for the purpose of recycling membrane-associated receptors such as sortilin and CI-MPR out of the endosome. Thus, patients with CLN5 loss-of-function variants may have defective recruitment of the retromer complex to the lysosome / endosome and disordered trafficking of membrane proteins out of these compartments as a result.
FAVariants: N/A
Rp1L1−/− mice display scattered OS disorganization, reduced electroretinogram amplitudes, and progressive photoreceptor degeneration, less severe and slower than in Rp1−/− mice. In single rods of Rp1L1−/−, photosensitivity is reduced, similar to that of Rp1−/−. While individual heterozygotes are normal
Six Novel Missense Mutations in the LDL Receptor-Related Protein 5 (LRP5) Gene in Different Conditions with an Increased Bone Density
PMID: 12579474
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.
The human U4/U6 snRNP contains 60 and 90kD proteins that are structurally homologous to the yeast splicing factors Prp4p and Prp3p
PMID: 9257651
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).
Retinitis pigmentosa
Case#: Jespersgaard_2019_Patient_167, 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.627+2T>G variant in the homozygous state.
ClinVar: 636057
gnomAD: The NM_000440.3(PDE6A):c.627+2T>G variant is not found in gnomAD v2.1.1.
VariantEvidence: The NM_000440.3(PDE6A):c.627+2T>G variant disrupts a canonical splice site in intron 2, but does not have experimental confirmation of exon skipping or frameshift.
CaseAddInfo: N/A
CasePMIDs: N/A
Retinitis Pigmentosa
Case#: Jespersgaard_2019_Patient_162, 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.1287G>A (p.Trp429Ter) and NM_000440.3(PDE6A):c.1054C>T (p.Gln352Ter) variants in the compound heterozygous state.
ClinVar: 636052, 636051
gnomAD: The NM_000440.3(PDE6A):c.1287G>A (p.Trp429Ter) and NM_000440.3(PDE6A):c.1054C>T (p.Gln352Ter) variants are not found in gnomAD v2.1.1.
VariantEvidence: NM_000440.3(PDE6A):c.1287G>A (p.Trp429Ter) and NM_000440.3(PDE6A):c.1054C>T (p.Gln352Ter) are nonsense variants in exons 10 and 7, respectively. They are predicted to result in nonsense-mediated decay or at least to respectively truncate the C-terminal ~59% or ~50% of the protein product.
CaseAddInfo: N/A
CasePMIDs: N/A
In this study, we have generated and characterized Oa1-deficient mice by gene targeting (KO). The KO males are viable, fertile and phenotypically indistinguishable from the wild-type littermates. Ophthalmologic examination shows hypopigmentation of the ocular fundus in mutant animals compared with wild-type. Analysis of the retinofugal pathway reveals a reduction in the size of the uncrossed pathway, demonstrating a misrouting of the optic fibres at the chiasm, as observed in OA1 patients. Microscopic examination of the RPE shows the presence of giant melanosomes comparable with those described in OA1 patients. Ultrastructural analysis of the RPE cells, suggests that the giant melanosomes may form by abnormal growth of single melanosomes, rather than the fusion of several, shedding light on the pathogenesis of ocular albinism.
ExperimentName: Mouse model with hemizygous disruption of the GPR143 ortholog Oa1
NonHumanModel: Mus musculus
GeneAlteration: A hemizygous mouse model of Oa1 knockout was generated by replacement of exon 1 (including the start codon) with a cassette to facilitate selection.
ModelPhenotype: HP:0007894 (Hypopigmentation of the fundus), HP:0025551 (Optic nerve misrouting), Giant melanosomes in retinal pigment epithelial cells
HumanPhenotype: HP:0000639 (Nystagmus), HP:0003593 (Infantile onset), HP:0007663 (Reduced visual acuity), HP:0001361 (Nystagmus-induced head nodding), HP:0000646 (Amblyopia), HP:0000483 (Astigmatism), HP:0000613 (Photophobia), normally pigmented skin and hair, HP:0005592 (Giant melanosomes in melanocytes), HP:0007750 (Hypoplasia of the fovea), HP:0007894 (Hypopigmentation of the fundus), HP:0025551 (Optic nerve misrouting)
ModelEvidence: Although the coat, eye color, and ERG responses of the mice were unaffected, the mice match the human patients in that they exhibit hypopigmentation of the fundus (Fig. 2), optic fiber misrouting at the chiasm, and expansion of individual melanosomes into giant melanosomes within cells of the RPE (Figures 2, 3). The mice match the mode of inheritance from the human patients.
ModelVariant: This model features disruption of Oa1 by knockout, but does not harbor a mutation equivalent to a variant from a human patient.
Oa1 knock-out: new insights on the pathogenesis of ocular albinism type 1
PMID: 11092754
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.
Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease
PMID: 28041643
GeneName: GNAT2
HGNC: 4394
Disease: achromatopsia 4
MonDO ID: MONDO_0013465
Inheritance: autosomal recessive
The significance of diminished IFT-A enrichment at the basal body is unclear. It may affect flagellar assembly kinetics because the mutant cells may not be able to readily utilize large quantities of IFT-A from the flagellar base during flagellar assembly. To test this, ift43Δ136 and ift140 mutants were deflagellated to allow flagellar regeneration. Consistent with a previous report [38], wild type cells and the mutant ift43Δ113 with an intact IFT43 conserved domain rapidly regenerated full length flagella (Fig 6A). The ift43Δ136 and ift140mutant cells could regenerate flagella to their original length but at a slower rate especially in theift140 mutant. Thus, the availability of the proper amount of IFT-A at the flagellar base may play a role in determining the rate of flagellar assembly.
ExperimentName: Chlamydomonas mutant model of IFT140 loss-of-function
NonHumanModel: Chlamydomonas reinhardtii
GeneAlteration: The Ift140 mutant model has disruption of the Chlamydomonas gene by insertion of the paromomycin resistance gene AphVIII between bases 8234 and 8235 of the IFT140 gene (in exon 21 of 28).
ModelPhenotype: The mutant exhibits short flagella due to slower flagellar regeneration as well as absence of IFT43 and IFT122 (IFT-A proteins) from the peri-basal body (shown by immunofluorescent co-localization with α-tubulin).
HumanPhenotype: The human patients exhibit the absence of cilia from fibroblasts
ModelEvidence: The cellular defects of the model in flagellar regeneration/assembly (Figures 6A,6C) parallel the absence of cilia from a high proportion of patient fibroblasts. The model also helps explain this defect by showing the underlying cause; the absence of IFT-A complex components from the peri-basal body region (Figure 5E-5F).
ModelVariant: The model does not feature any of the variants observed in human patients.
Functional exploration of the IFT-A complex in intraflagellar transport and ciliogenesis
PMID: 28207750
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.
mutations
Case#: Holmberg_Patient_6, male, age 2 at onset and age 13 at death, Dutch origin
CasePresentingHPOs: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0011463 (Childhood onset), HP:0001268 (Mental deterioration), HP:0000572 (Visual loss), HP:0001251 (Ataxia), HP:0011421 (Death in adolescence), HP:0002540 (Inability to walk), HP:0001250 (Seizure), HP:0000550 (Undetectable electroretinogram), HP:0012018 (EEG with temporal focal spikes), HP:0100952 (Enlarged sylvian cistern), HP:0006855 (Cerebellar vermis atrophy), HP:0002198 (Dilated fourth ventricle), HP:0033725 (Thin corpus callosum), HP:0030891 (Periventricular white matter hyperdensities), HP:0012690 (T2 hypointense thalamus)
CaseHPOFreeText: This patient exhibited the most rapid clinical course from the group of 8 patients. Age of onset was 2, while mental decline was present at age 3 and visual deterioration at age 5. Ataxia, seizures, and abolished electroretinogram were found at age 7. Loss of independent walking occurred at age 8. Posterior EEG spikes in response to low-frequency photic stimuli were observed. T2-weighted images showed increased signal intensity of the periventricular white matter and posterior limb of the capsula interna. The thalamus had abnormally low signal intensity compared to the putamen, caudate nuclei, and white matter.
CaseNotHPOs: HP:0001312 (Giant somatosensory evoked potentials)
CaseNotHPOFreeText: Flash visual evoked potential (fVEP) was found to be normal at age 7.
CasePreviousTesting: Other than clinical phenotype characterization, it is not clear what genotype tests preceded CLN5 sequencing.
CaseMethod1: N/A
CaseMethod2: N/A
CaseGenotypingMethod: Each exon of CLN5 was PCR-amplified and Sanger sequenced in both directions.
Variant: The patient is homozygous for the NM_006493.4(CLN5):c.688G>A (p.Asp230Asn) variant.
ClinVar: 2566 (homozygous)
gnomAD: The maximum allele frequency of the NM_006493.4(CLN5):c.688G>A (p.Asp230Asn) variant is 0.00005437 (within the East Asian population, with no homozygous occurrences). https://gnomad.broadinstitute.org/variant/13-77574715-G-A
VariantEvidence: NM_006493.4(CLN5):c.688G>A (p.Asp230Asn) is a recurring missense variant that has been previously shown to introduce an additional N-glycosylation site within the C-terminal region of CLN5 (PMID:20052765) and to disturb its localization to the lysosome (PMID:20052765).
CaseAddInfo: N/A
CasePMIDs: N/A
mutation
Case#: Holmberg_Patient_8, female, age 3 at onset and age 19 at time of study, Swedish origin
CasePresentingHPOs: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0011463 (Childhood onset), HP:0001268 (Mental deterioration), HP:0000572 (Visual loss), HP:0001251 (Ataxia), HP:0002540 (Inability to walk), HP:0001250 (Seizure), HP:0012018 (EEG with temporal focal spikes), HP:0100952 (Enlarged sylvian cistern), HP:0006855 (Cerebellar vermis atrophy), HP:0002198 (Dilated fourth ventricle), HP:0033725 (Thin corpus callosum), HP:0030891 (Periventricular white matter hyperdensities), HP:0012690 (T2 hypointense thalamus), HP:0001312 (Giant somatosensory evoked potentials), HP:0002059 (Cerebral atrophy), HP:0001272 (Cerebellar atrophy)
CaseHPOFreeText: Age of onset was 3, while mental decline was found at age 7. Visual deterioration and Seizures developed at age 8. Ataxia and Giant flash visual evoked potentials had onset at age 9. Loss of independent walking occurred at age 10. Posterior EEG spikes in response to low-frequency photic stimuli were observed. T2-weighted images showed increased signal intensity of the periventricular white matter and posterior limb of the capsula interna. The thalamus had abnormally low signal intensity compared to the putamen, caudate nuclei, and white matter. Cerebral atrophy was slight at age 8.9 years, but had progressed to severe cerebral and cerebellar atrophy by age 17.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Other than clinical phenotype characterization, it is not clear what genotype tests preceded CLN5 sequencing.
CaseMethod1: N/A
CaseMethod2: N/A
CaseGenotypingMethod: Each exon of CLN5 was PCR-amplified and Sanger sequenced in both directions.
Variant: The patient is a compound heterozygote harboring the NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) and NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) variants.
ClinVar: 2565, 56543
gnomAD: The maximum allele frequency of the NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) variant is 0.00005132 (within the European non-Finnish population, with no homozygous occurrences). https://gnomad.broadinstitute.org/variant/13-77566311-G-A The maximum allele frequency of the NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) variant is 0.00007033 (within the European non-Finnish population, with no homozygotes) https://gnomad.broadinstitute.org/variant/13-77570218-A-AC
VariantEvidence: NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) is a recurring nonsense variant that is predicted to trigger nonsense-mediated decay of CLN5. NM_006493.4(CLN5):c.522dup (p.Trp175LeufsTer30) is a frameshift variant, is predicted to disrupt ~51% of the protein product, and exhibits defective localization to the ER rather than the lysosome (PMID:20052765).
CaseAddInfo: N/A
CasePMIDs: N/A
eight patients
GroupName: Holmberg_Group_1
GroupPresentingHPOs: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0011463 (Childhood onset), HP:0001268 (Mental deterioration), HP:0000572 (Visual loss), HP:0001251 (Ataxia), HP:0012018 (EEG with temporal focal spikes), HP:0100952 (Enlarged sylvian cistern), HP:0006855 (Cerebellar vermis atrophy), HP:0002198 (Dilated fourth ventricle), HP:0033725 (Thin corpus callosum), HP:0030891 (Periventricular white matter hyperdensities), HP:0012690 (T2 hypointense thalamus)
GroupHPOFreeText: Posterior EEG spikes in response to low-frequency photic stimuli were observed. T2-weighted images showed increased signal intensity of the periventricular white matter and posterior limb of the capsula interna. The thalamus had abnormally low signal intensity compared to the putamen, caudate nuclei, and white matter.
GroupNotHPOs: N/A
GroupNotHPOFreeText: N/A
NumberMales: 4
NumberFemales: 4
CountryOrigin: Finland / Sweden / Netherlands
Ethnicity: Finnish / Swedish / Dutch
Race: Not mentioned
AgeRange: 2-4 years old at onset, 7-19 years old at time of study
TotalNumber: 8
FamilyInfo: 0
NoFamily: 8
VariantCount: 8
NonVariant: 0
OtherVariant: 0
GroupPreviousTesting: Other than clinical phenotype characterization, it is not clear what genotype tests preceded CLN5 sequencing.
GroupMethod1: N/A
GroupMethod2: N/A
GroupGenotypingMethod: Each exon of CLN5 was PCR-amplified and Sanger sequenced in both directions.
GroupAddInfo: N/A
four
Case#: Holmberg_Patient_4, female, age 3 at onset and age 13 at time of study, Finnish origin
CasePresentingHPOs: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0011463 (Childhood onset), HP:0001268 (Mental deterioration), HP:0000572 (Visual loss), HP:0001251 (Ataxia), HP:0002540 (Inability to walk), HP:0001250 (Seizure), HP:0000550 (Undetectable electroretinogram), HP:0012018 (EEG with temporal focal spikes), HP:0100952 (Enlarged sylvian cistern), HP:0006855 (Cerebellar vermis atrophy), HP:0002198 (Dilated fourth ventricle), HP:0033725 (Thin corpus callosum), HP:0030891 (Periventricular white matter hyperdensities), HP:0012690 (T2 hypointense thalamus), HP:0001312 (Giant somatosensory evoked potentials)
CaseHPOFreeText: Age of onset was 3, while visual deterioration was found at age 6. Mental decline was found at age 7, while abolished ERG and Giant flash visual evoked potentials were present at age 8. Ataxia, Seizures, and Loss of independent walking occurred at age 11. Posterior EEG spikes in response to low-frequency photic stimuli were observed. T2-weighted images showed increased signal intensity of the periventricular white matter and posterior limb of the capsula interna. The thalamus had abnormally low signal intensity compared to the putamen, caudate nuclei, and white matter.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Other than clinical phenotype characterization, it is not clear what genotype tests preceded CLN5 sequencing.
CaseMethod1: N/A
CaseMethod2: N/A
CaseGenotypingMethod: Each exon of CLN5 was PCR-amplified and Sanger sequenced in both directions.
Variant: The patient is homozygous for the NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) variant.
ClinVar: 2565 (homozygous)
gnomAD: The maximum allele frequency of the NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) variant is 0.00005132 (within the European non-Finnish population, with no homozygous occurrences). https://gnomad.broadinstitute.org/variant/13-77566311-G-A
VariantEvidence: NM_006493.4(CLN5):c.78G>A (p.Trp26Ter) is a recurring nonsense variant that is predicted to trigger nonsense-mediated decay of CLN5.
CaseAddInfo: N/A
CasePMIDs: N/A
We created an RPGR-deficient murine model by gene knockout. In the mutant mice, cone photoreceptors exhibit ectopic localization of cone opsins in the cell body and synapses and rod photoreceptors have a reduced level of rhodopsin. Subsequently, both cone and rod photoreceptors degenerate. RPGR was found normally localized to the connecting cilia of rod and cone photoreceptors. These data point to a role for RPGR in maintaining the polarized protein distribution across the connecting cilium by facilitating directional transport or restricting redistribution. The function of RPGR is essential for the long-term maintenance of photoreceptor viability.
ExperimentName: Mouse knockout model of Rpgr loss-of-function
NonHumanModel: Mus musculus
GeneAlteration: The model has targeted hemizygous (male) or biallelic (female) disruption of the mouse Rpgr gene by insertion of a neomycin resistance cassette to replace exons 4 through 6 with a resistance cassette and generate a null variant.
ModelPhenotype: HP:0030612 (Abnormal retinal morphology on macular OCT), partial mislocalization of blue and green cone opsins to the inner segment, reduced rhodopsin content in the outer segment, HP:0000546 (Retinal degeneration), HP:0030609 (Photoreceptor layer loss on macular OCT), HP:0030610 (Photoreceptor outer segment loss on macular OCT), disorganization of disk membranes, normal connecting cilia morphology, HP:0030483 (Reduced amplitude of dark-adapted bright flash electroretinogram a-wave), HP:0008275 (Abnormal light-adapted electroretinogram),
HumanPhenotype: HP:0007642 (Congenital stationary night blindness), HP:0007994 (Peripheral visual field loss), HP:0000529 (Progressive visual loss), HP:0000365 (Hearing impairment), HP:0002205 (Recurrent respiratory infections), HP:0011109 (Chronic sinusitis), HP:0000388 (Otitis media), HP:0002837 (Recurrent bronchitis), HP:0012263 (Immotile cilia), HP:0005938 (Abnormal respiratory motile cilium morphology)
ModelEvidence: The model has been well-characterized at the ocular level and triggers molecular and photoreceptor cell defects (Figures 4a, 4b, 5, 6, 7a, and 7b) that are consistent with human patient features such as night blindness, central visual field loss, and peripheral visual field loss.
ModelVariant: The model does not feature a variant equivalent to one observed in human patients.
A retinitis pigmentosa GTPase regulator (RPGR)- deficient mouse model for X-linked retinitis pigmentosa (RP3)
PMID: 10725384
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.
P09 GC29680 c.3399T>G p.Tyr1133* Homozygous
Case#: Georgiou_2024_Family_GC29680_Proband_P09, female, reported at age 30 years, family origin reported as from Bangladesh
CasePresentingHPOs: HP:0011003 (High myopia), HP:0030558 (Best corrected visual acuity 0.5 LogMAR)
CaseHPOFreeText: BCVA began at 0.39 logMAR and progressed to 0.54 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.3399T>G (p.Tyr1133Ter) variant in the homozygous state.
ClinVar ID: 3675731
gnomAD: The variant is found in gnomAD version 4.1.1 at a frequency of 0.00001098 (1 / 91070) in the South Asian population https://gnomad.broadinstitute.org/variant/chr10-47357112-T-G?dataset=gnomad_r4
VariantEvidence: NM_002900.3(RBP3):c.3399T>G (p.Tyr1133Ter) is a nonsense variant within exon 4 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
P06 GC19393 c.160C>T p.Gln54* Homozygous
Case#: Georgiou_2024_Family_GC19393_Proband_P06, female, reported at age 14 years, family origin reported as from Pakistan
CasePresentingHPOs: HP:0011003 (High myopia), HP:0030555 (Best corrected visual acuity 0.2 LogMAR)
CaseHPOFreeText: BCVA began at 0.20 logMAR and progressed to 0.30 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.160C>T (p.Gln54Ter) variant in the homozygous state.
ClinVar ID: 964958
gnomAD: The variant is found in gnomAD version 4.1.1 at a frequency of 0.0003184 (29 / 91094) in the South Asian population https://gnomad.broadinstitute.org/variant/10-47348644-C-T?dataset=gnomad_r4
VariantEvidence: NM_002900.3(RBP3):c.160C>T (p.Gln54Ter)) is a nonsense 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
Aberrant RNA splicing is the major pathogenic effect in a knock-in mouse model of the dominantly inherited c.1430A>G human RPE65 mutation
PMID: 30628748
Gene: RPE65
HGNC: 10294
Disease: Retinitis pigmentosa 87 with choroidal involvement
MONDO: 0032873
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 8,000 and 1 in 27,000). The prevalence of Retinitis pigmentosa 87 with choroidal involvement is considered to be much lower.
Penetrance: Incomplete penetrance, estimated at 80%
A stop sequence at codon 258 exists in a family with adult vitelliform macular dystrophy.
Case#: Wells_1993_Proband_III/5, female, age 44 years at time of first examination, family origin not reported
CasePresentingHPOs: Adult onset HP:0003581, Visual impairment HP:0000505, Subretinal deposits HP:0031528, Abnormal light-adapted single flash electroretinogram HP:0030472.
CaseHPOFreeText: The proband has been diagnosed with adult vitelliform macular dystrophy, with onset in the mid-thirties. Foveal deposits are small, yellow, and at the RPE level.
CaseNotHPOs: Abnormal light-adapted flicker electroretinogram HP:0030473
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous testing consisted of screening of the RHO locus for disease-causing variants.
CaseMethod1: Sanger sequencing of PRPH2
CaseMethod2: N/A
CaseGenotypingMethod: Previous testing of this family consisted of screening of the RHO locus for variants causing RP, with negative results. Genotyping was performed by Sanger sequencing of the PCRs product to identify the variant.
Variant: The proband harbors the NM_000322.5(PRPH2):c.774C>A (p.Tyr258Ter) variant in the heterozygous state.
ClinVar ID: 98707
gnomAD: The NM_000322.5(PRPH2):c.774C>A (p.Tyr258Ter) variant was not found in gnomAD v4.0.0.
VariantEvidence: NM_000322.5(PRPH2):c.774C>A (p.Tyr258Ter) is a nonsense variant in exon 2 of 3 that is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 26% of the protein product.
CaseAddInfo: Although the proband is the only family member genotyped and examined by the authors, her father was confirmed to be similarly affected. Family consanguinity was not reported.
CasePMIDs: N/A
deletion
Case#: Xin_Patient_9, sex not mentioned, age 6 at onset, U.S. nationality, Egyptian ethnicity
CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0011463 (Childhood onset), HP:0003736 (Autophagic vacuoles)
CaseHPOFreeText: Motor difficulty was the phenotype at presentation (age 6). Cognitive regression, Seizures, and Visual loss had onset at age 7. EM finding of vacuoles was made specifically in muscle.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.
CaseMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing
CaseMethod2: as mentioned
CaseGenotypingMethod: CLN5 genotyping was performed by PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.
Variant: The patient is believed to be homozygous for the NM_006493.4(CLN5):c.772del p.Arg258GlufsTer29 variant.
ClinVar: 56546 (homozygous)
gnomAD: The NM_006493.4(CLN5):c.772del p.Arg258GlufsTer29 variant is absent from gnomAD.
VariantEvidence: NM_006493.4(CLN5):c.772del p.Arg258GlufsTer29 is a frameshift variant that disrupts ~28% of the protein product.
CaseAddInfo: Parents have not been subjected to genotyping, so homozygosity of variants is assumed. This conclusion was supported by failure to detect a deletion, and by family history of consanguinity.
CasePMIDs: N/A
CLN5 mutations
Case#: Xin_Patient_2, sex not mentioned, age 5-6 at onset, U.S. nationality, admixed European non-Finnish ethnicity
CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0011463 (Childhood onset), HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material)
CaseHPOFreeText: Seizure was the phenotype at presentation (age 5). Motor difficulty, visual loss, and cognitive regression had onset at age 6.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.
CaseMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing
CaseMethod2: as mentioned
CaseGenotypingMethod: CLN5 genotyping was performed by PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.
Variant: The patient harbors the NM_006493.4(CLN5):c.524G>A (p.Trp175Ter) and NM_006493.4(CLN5):c.760_947del (p.Thr254CysfsTer10) variants.
ClinVar: 56544
CAID: CA2017997733
gnomAD: Maximum allele frequency for NM_006493.4(CLN5):c.524G>A (p.Trp175Ter) is 0.00003517 (in the European non-Finnish population, no homozygotes). https://gnomad.broadinstitute.org/variant/13-77570221-G-A The NM_006493.4(CLN5):c.760_947del (p.Thr254CysfsTer10) variant is not found in gnomAD.
VariantEvidence: NM_006493.4(CLN5):c.524G>A (p.Trp175Ter) is a nonsense variant that results in truncation of approximately 51% of the protein product. The NM_006493.4(CLN5):c.760_947del (p.Thr254CysfsTer10) variant triggers a frameshift that affects the final 106 amino acids (approximately 29%) of the protein product. While neither variant is predicted to trigger NMD, the C-terminal region disrupted in both cases has been shown to be glycosylated and is important for proper localization of the protein (PMID:19309691).
CaseAddInfo: Parents do not appear to have been genotyped, so it is not clear whether the two variants are confirmed to be in trans.
CasePMIDs: N/A
not previously described
Case#: Xin_Patient_7, sex not mentioned, age 4 at onset, U.S. nationality, Chinese ethnicity
CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0011463 (Childhood onset)
CaseHPOFreeText: Visual loss was the phenotype at presentation (age 4). Motor difficulty (age 5), Cognitive regression (age 5), and Seizure (age 6) had later onset.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.
CaseMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing
CaseMethod2: as mentioned
CaseGenotypingMethod: CLN5 genotyping was performed by PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.
Variant: The patient harbors the NM_006493.4(CLN5):c.473G>C (p.Trp158Ser) and NM_006493.4(CLN5):c.924_925del (p.Leu309AlafsTer4) variants.
ClinVar: 56542, 56526
gnomAD: Both the NM_006493.4(CLN5):c.473G>C (p.Trp158Ser) and NM_006493.4(CLN5):c.924_925del (p.Leu309AlafsTer4) variants are absent from gnomAD.
VariantEvidence: NM_006493.4(CLN5):c.924_925del (p.Leu309AlafsTer4) is a frameshift variant that disrupts approximately 14% of the protein product. The NM_006493.4(CLN5):c.473G>C (p.Trp158Ser) missense variant affects a conserved residue but does not have other evidence of gene impact.
CaseAddInfo: Parents do not appear to have been genotyped, so it is not clear whether the two variants are confirmed to be in trans.
CasePMIDs: N/A
We have identified a novel ENU mutant allele of Ift140, which causes a mid-gestation embryonic lethal phenotype in homozygous mutant mice. Mutant embryos exhibit a range of phenotypes including exencephaly and spina bifida, craniofacial dysmorphism, digit anomalies, cardiac anomalies and somite patterning defects.
ExperimentName: Mouse homozygous mutant model of partial IFT140 loss-of-function
NonHumanModel: Mus musculus
GeneAlteration: The Cauli mouse model has biallelic disruption of the mouse Ift140 gene introduced by mutagenesis using N-ethyl-N-nitrosourea. The mutation is a missense change is c.2564T>A (p.Ile855Lys) in Ift140.
ModelPhenotype: HP:0034241 (Prenatal death), HP:0030769 (Exencephaly), HP:0002414 (Spina bifida), HP:0001999 (Abnormal facial shape), HP:0002648 (Abnormality of calvarial morphology), HP:0011297 (Abnormal digit morphology), HP:0001627 (Abnormal heart morphology), HP:0033334 (Abnormal embryonic development, specifically defects in somite patterning), HP:0000528 (Anophthalmia), HP:0001829 (Foot polydactyly), HP:0000194 (Open mouth), HP:0000772 (Abnormal rib morphology), HP:0000896 (Rib exostoses), HP:0001789 (Hydrops fetalis), HP:0001654 (Abnormal heart valve morphology), HP:0010290 (Short hard palate),
HumanPhenotype: HP:0001156 (Brachydactyly), HP:0010579 (Cone-shaped epiphysis), HP:0000556 (Retinal dystrophy), HP:0001591 (Bell-shaped thorax), HP:0000773 (Short ribs), HP:0000107 (Renal cyst), HP:0001252 (Hypotonia), HP:0001263 (Global developmental delay), HP:0001363 (Craniosynostosis), HP:0005054 (Metaphyseal spurs), HP:0010454 (Acetabular spurs), HP:0000083 (Renal insufficiency), HP:0002093 (Respiratory insufficiency), absent cilia in fibroblasts
ModelEvidence: The mode of inheritance in this model matches the biallelic/homozygous mode of inheritance observed in human disease. While the defects in the mouse model are more severe than those of the human patients, shared features include rib cage anomalies (Figure 2), digit anomalies (Figure 4), disruption of eye development (fully penetrant, described in text only), and severe morphological anomalies of the primary cilia in the limb buds (Figure 1G). While the model was generated using a mutagen, it is important to note that the targeted homozygous null mutant in Ift140 recapitulates the features of the model, albeit with enhanced severity. This confirms that the model's mechanism of pathogenicity is incomplete loss of Ift140 function. The localization of Ift140 protein to the base and tip of primary cilia in the limb bud is also consistent with the known function in humans (Figure 5F).
ModelVariant: The model does not feature any of the variants observed in human patients. Instead, the mutation is a missense change, c.2564T>A (p.Ile855Lys) in Ift140. The corresponding residue in human IFT140 is Thr854.
shRNA targeting of Kir7.1 inhibited mRNA expression and reduced ERG After demonstrating that Kir7.1 protein is primarily expressed in RPE cells, we sought to determine whether the RPE Kir7.1 channel contributes to the ERG. We delivered a specific shRNA lentiviral particle to the mouse vitreal chamber by micro injection to inhibit Kcnj13 gene expression. Seven days after shRNA injection, eyes were harvested and RPE cells isolated. PCR amplification of Kcnj13 in RPE cells did not reveal a product from the shRNA injected mouse eye (Fig. 3A Lanes 3), whereas in the contralateral eye that received saline injection, a 653 bp band corresponding to the Kcnj13 transcript was present (Fig. 3A Lane 5). Housekeeping gene ß-actin transcript was detected as a 248 bp band in both samples (Fig. 3A Lanes 4 &6). We did not detect either Kir7.1 or actin in negative control experiments (Fig. 3A Lanes 7 & 8). Kir7.1 shRNA inhibition was able to reduce Kcnj13 mRNA expression by an average of 73.62 ± 14.47% (Fig. 3B).
Mouse model based on ERG defects induced by Kcnj13 shRNA injection (packaged in lentiviral particles)
A mouse model for Finnish variant late infantile neuronal ceroid lipofuscinosis, CLN5, reveals neuropathology associated with early aging
PMID: 15459177
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
Pedigree AR534; cosegregation of ABCR mutations with retinal disease.
Case#: Shroyer_1999_Proband_AR534-07, female, age 68 years at time of diagnosis, family origin from the United States (Utah or Boston)
CasePresentingHPOs: HP:0000505 (Visual impairment), HP:0000608 (Macular degeneration), HP:0003584 (Late onset)
CaseHPOFreeText: The proband has been diagnosed with exudative age-related macular degeneration.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: The proband and her family members have been genotyped by heteroduplex and SSCP analysis of ABCA4 PCR products, followed by Sanger sequencing-based confirmation.
CaseMethod1: SSCP
CaseMethod2: Sanger sequencing of ABCA4
CaseGenotypingMethod: The proband and her family members have been genotyped by heteroduplex and SSCP analysis of ABCA4 PCR products, followed by Sanger sequencing-based confirmation.
Variant: The proband harbors the NM_000350.3(ABCA4):c.4139C>T (p.Pro1380Leu) variant in the heterozygous state.
ClinVar ID: 7904
gnomAD: The variant is found in gnomAD v4.1.0 at frequencies of 0.0003059 in the European (non-Finnish) population and 0.001723 in the Ashkenazi Jewish population. https://gnomad.broadinstitute.org/variant/1-94031110-G-A?dataset=gnomad_r4
VariantEvidence: NM_000350.3(ABCA4):c.4139C>T (p.Pro1380Leu) is a missense variant without functional evidence of a damaging impact on ABCA4.
CaseAddInfo: The proband is the grandmother of four patients with a diagnosis of Stargardt disease. Her 52-year-old daughter carries the same variant but is unaffected (normal fundus).
CasePMIDs: N/A
Proteoglycan IMPG2 Shapes the Interphotoreceptor Matrix and Modulates Vision
PMID: 32265257
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.
A Novel Tissue Inhibitor of Metalloproteinases-3 Mutation Reveals a Common Molecular Phenotype in Sorsby's Fundus Dystrophy
PMID: 10854443
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
RP
Case#: Olivier_2021_Family_C_Proband_II:1, female, age 48 years at the time of diagnosis, national origin reported as Spanish
CasePresentingHPOs: HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0030329 (Retinal thinning), HP:0007737 (Bone spicule pigmentation of the retina)
CaseHPOFreeText: The proband was diagnosed with moderate retinitis pigmentosa at age 48 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 gene panel testing and Sanger sequencing-based confirmation
CaseMethod2: Haplotype analysis using the microsatellite markers D6S1622, D6S456, D6S1589 and D6S251, spanning a 7.2-Mb region surrounding IMPG1.
CaseGenotypingMethod: Genotyping is not entirely clear but has at least included panel-based analysis of the IMPG1 locus, Sanger sequencing-based confirmation, and haplotype analysis of the multiple families harboring the variant.
Variant: The affected family members harbor the NM_001563.4:c.1824+1G>A variant in the heterozygous state.
ClinVar ID: 1240018
gnomAD: This variant is found in gnomAD v2.1.1 at a frequency of 0.00002980 (1 / 33554 alleles total in the Latino / Admixed American population. https://gnomad.broadinstitute.org/variant/6-76660278-C-T
VariantEvidence: NM_001563.4:c.1824+1G>A is an intronic variant disrupting a canonical splice site in intron 13 (of the 17-exon gene), with unknown consequences for IMPG1 splicing.
CaseAddInfo: This family helps establish the incomplete penetrance of the variant, as the patient's carrier mother was clinically asymptomatic with no retinal vessel abnormalities, despite the presence of hard drusen-like deposits in the macula.
CasePMIDs: N/A
VMD
Case#: Olivier_2021_Family_B_Proband_II:2, female, age not specified, ethnic origin reported as French
CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0030643 (Vitelliform-like retinal lesions), HP:0011506 (Choroidal neovascularization),
CaseHPOFreeText: The patient has a diagnosis of vitelliform macular dystrophy, and reportedly has a hyperreflective deposit in one eye.
CaseNotHPOs: HP:0000512 (Abnormal electroretinogram), HP:0030454 (Abnormal electrooculogram)
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 gene panel testing and Sanger sequencing-based confirmation
CaseMethod2: Haplotype analysis using the microsatellite markers D6S1622, D6S456, D6S1589 and D6S251, spanning a 7.2-Mb region surrounding IMPG1.
CaseGenotypingMethod: Genotyping is not entirely clear but has at least included panel-based analysis of the IMPG1 locus, Sanger sequencing-based confirmation, and haplotype analysis of the multiple families harboring the variant.
Variant: The affected family members harbor the NM_001563.4:c.1824+1G>A variant in the heterozygous state.
ClinVar ID: 1240018
gnomAD: This variant is found in gnomAD v2.1.1 at a frequency of 0.00002980 (1 / 33554 alleles total in the Latino / Admixed American population. https://gnomad.broadinstitute.org/variant/6-76660278-C-T
VariantEvidence: NM_001563.4:c.1824+1G>A is an intronic variant disrupting a canonical splice site in intron 13 (of the 17-exon gene), with unknown consequences for IMPG1 splicing.
CaseAddInfo: This family has helped establish the incomplete penetrance of the variant, as the patient's two sisters were asymptomatic carriers with normal fundus findings at ages 45 and 50 years respectively. The patient's 70-year-old mother was also a carrier and exhibited low vision.
CasePMIDs: N/A
unusual
Case: Felbor_1995_Family_1_patient_1, gender and age not specified, German-Czech family origin
DiseaseAssertion: Sorsby's fundus dystrophy
FamilyInfo: Family pedigree (from microsatellite-based linkage testing) mapping the disease locus to chr22q13-qter is shown in Figure 1.
CasePresentingHPOs: HP:0030666 (Retinal neovascularization), HP:0007777 (Chorioretinal scar), HP:0000603 (Central scotoma), HP:0000556 (Retinal dystrophy), HP:0007737 (Bone spicule pigmentation of the retina), HP:0000630 (Abnormal retinal artery morphology), HP:0030491 (Choriocapillaris atrophy), HP:0007994 (Peripheral visual field loss), HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0008275 (Abnormal light-adapted electroretinogram)
CaseHPOFreeText: Patients were considered to exhibit early-onset SFD with a mean age of 25. The presenting symptom was central subretinal neovascularisation, which preceded extensive scarring. Second eye involvement generally occurred months later, indicating rapid progression. Retinal dystrophy was reported to be tapetal. Intraretinal arteries were attenuated. Dark adaptation was decreased.
CaseNOTHPOs: N/A
CaseNOTHPOFreeText: N/A
CasePreviousTesting: Genetic linkage testing / genotyping of affected and unaffected family members with three microsatellite markers that were previously associated with SFD and that flank the TIMP3 locus. This was followed by single-stranded conformational polymorphism (SSCP) of all five TIMP3 exons, detecting a mobility shift in exon 5.
CaseGenotypingMethod: Bidirectional Sanger sequencing of exon 5 PCR products from two affected individuals.
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: NM_000362.5(TIMP3):c.536C>G, (p.Ser179Cys) is a missense variant predicted to substitute a new cysteine residue into exon 5.
ClinVar: 12678
gnomAD: Variant is absent from gnomAD.
VariantEvidence: This variant substitutes an additional cysteine residue into the C-terminal region encoded by TIMP3 exon 5. Additional variant evidence is presented in PMID:10854443 and PMID:16223891.
A novel homozygous nonsense mutation in CABP4 causes congenital cone-rod synaptic disorder
PMID: 19074807
Gene: CABP4
HGNC: 1386
Disease: cone-rod synaptic disorder, congenital nonprogressive
MONDO: 0012490
InheritancePattern: autosomal recessive
Prevalence: The prevalence of the Åland eye disease or incomplete congenital stationary night blindness phenotype was estimated at 1 in 22,000 based on a Danish male cohort, with CABP4 variants specifically responsible for 1 out of 35 cases (PMID: 28002560).
Penetrance: Penetrance appears to be 100% among the reported individuals harboring biallelic disease-causing CABP4 variants.
One of the mutations affected the initiating methionine codon (Met1Thr, family 9404)
Case#: Morimura_1998_Family_9404_Patient_II-3, male, age and family origin not specified
CasePresentingHPOs: HP:0000546 (Retinal degeneration)
CaseHPOFreeText: While specific phenotypes are not provided, the initial diagnosis of Leber congenital amaurosis indicates that the proband was either born blind or lost vision within a period of months after birth.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: All 14 RPE65 exons and flanking sequences were PCR-amplified and subjected to single-strand conformation polymorphism analysis (SSCA).
CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA
CaseMethod2: Sanger sequencing of all 14 exons of RPE65
CaseGenotypingMethod: PCR-amplified exons identified by SSCA as candidates to harbor variants were subjected to Sanger sequencing.
Variant: The proband is a homozygote within the RPE65 locus, harboring the NM_000329.3(RPE65):c.2T>C (p.Met1Thr) variant.
ClinVar: 98861 (homozygous)
gnomAD: The NM_000329.3(RPE65):c.2T>C (p.Met1Thr) variant was not found within gnomAD.
VariantEvidence: NM_000329.3(RPE65):c.2T>C (p.Met1Thr) is a missense variant that disrupts the start codon and is therefore predicted to have gene impact.
CaseAddInfo: Other family members were not genotyped, and potential consanguinity between the parents was not reported.
CasePMIDs: N/A
IVS6–2A->T (AG to TG)
Case#: Morimura_1998_Family_0748_Patient_II-1, female, age and family origin not specified
CasePresentingHPOs: HP:0000546 (Retinal degeneration)
CaseHPOFreeText: While specific phenotypes are not provided, the initial diagnosis of Leber congenital amaurosis indicates that the proband was either born blind or lost vision within a period of months after birth.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: All 14 RPE65 exons and flanking sequences were PCR-amplified and subjected to single-strand conformation polymorphism analysis (SSCA).
CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA
CaseMethod2: Sanger sequencing of all 14 exons of RPE65
CaseGenotypingMethod: PCR-amplified exons identified by SSCA as candidates to harbor variants were subjected to Sanger sequencing.
Variant: The proband is a homozygote within the RPE65 locus, harboring the NM_000329.3(RPE65):c.643+2T>A variant.
ClinVar: 940479 (homozygous)
gnomAD: The NM_000329.3(RPE65):c.643+2T>A variant is not found within gnomAD.
VariantEvidence: NM_000329.3(RPE65):c.643+2T>A is an intron 6 variant strongly predicted to disrupt a canonical splice donor site (with a delta score of 0.98).
CaseAddInfo: While the variant is known to be homozygous, the proband's parents have not been genotyped. The potential consanguinity of the parents was not mentioned.
CasePMIDs: N/A
We therefore investigated potential GPR143 interaction partners, with a focus on the melanogenic enzyme tyrosinase. GPR143 co-immunoprecipitated with tyrosinase, while confocal microscopy demonstrated colocalization of the proteins. Furthermore, tyrosinase localized to the plasma membrane when co-expressed with a GPR143 trafficking mutant. The physical interaction between the proteins was confirmed using Fluorescence Resonance Energy Transfer.
ExperimentName: GPR143 interacts with TYR by co-IP and FRET
InteractingGene: TYR, which is implicated in oculocutaneous albinism types 1A and 1B
InteractionType: Physical
InteractionMethod: Co-immunoprecipitation and FRET were both performed with positive results.
InteractionEvidence: Co-IP of the exogenously expressed GPR143 fusion protein or endogenous TYR found that IP of one protein pulls down the other as well (Figure 2). This was confirmed by fluorescent resonance energy transfer experiments (Figures 4 and 5). Use of a mislocalizing GPR143 mutant control showed that TYR localization appears to be GPR143-dependent (Figures 3 and 4).
Expression and characterization of the IPM 150 gene (IMPG1) product, a novel human photoreceptor cell-associated chondroitin-sulfate proteoglycan
PMID: 10601738
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.
three
Case#: Meindl_1996_Family_RP49_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.644G>T (p.Gly215Val) variant in the hemizygous state.
ClinVar: 98794
gnomAD: The variant was not found in gnomAD v.2.1.1.
VariantEvidence: NM_001034853.2(RPGR):c.644G>T (p.Gly215Val) is a missense variant in exon 7 of 15 and has been shown to disrupt the ability of the protein product to interact with PDE6D, INPP5E, and RPGRIP1L (PMID: 30622176, Figure 4).
CaseAddInfo: The proband is a member of Family RP49.
CasePMIDs: N/A
linkage
FamilyLabel: Meindl_1996_Family_F47
Family#PresentingHPOs: N/A
FamilyPresentingHPOFreeText: Affected family members have been diagnosed with retinitis pigmentosa, with an X-linked pattern of inheritance.
FamilyNotHPOs: N/A
FamilyNotHPOFreeText: N/A
CountryOrigin: Not specified
Ethnicity: Not specified
Race: Not specifically mentioned
Family#PreviousTesting: 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.
Family#Method1: Hybridization analysis of amplified cDNA fragments from the RPGR locus to look for deletions, and SSCP analysis to look for point mutations
Family#Method2: Sanger sequencing of the RPGR locus
Family#GenotypingMethod: 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.
Affected: 3
Unaffected: N/A
Segregations: 8 segregations are shown by the pedigree in Figure 6.
PublishedLOD: N/A
eLOD: 2.4
AddSegregationInfo: N/A
ProbandLabel: Meindl_1996_Family_F47_Proband
Variant: The affected family members harbor the NM_001034853.2(RPGR):c.294C>A (p.His98Gln) variant in the hemizygous state.
ClinVar: 98775
gnomAD: The variant was not found in gnomAD v.2.1.1.
VariantEvidence: NM_001034853.2(RPGR):c.294C>A (p.His98Gln) is a missense variant and does not have associated evidence of impact on RPGR function.
FamilyAddInfo: N/A
FamilyPMIDs: N/A
ON pathway mutations increase susceptibility to form-deprivation myopia
PMID: 26072023
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.
Gene Therapy in Opn1mw−/−/Opn1sw−/− Mice and Implications for Blue Cone Monochromacy Patients with Deletion Mutations
PMID: 35272502
Gene: OPN1LW
HGNC: 9936
Disease: protan color blindness
MONDO: 0010565
InheritancePattern: X-linked
Prevalence: The overall prevalence of protan color blindness is approximately 1% in males, which is higher than that of blue cone monochromacy (~1 in 100,000, PMID: 35759666).
Penetrance: Known disease-causing alleles appear to be almost completely penetrant in males (PMID: 21167193).
A distinct vitreo-retinal dystrophy with early-onset cataract from recessive KCNJ13 mutations
PMID: 25475713
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.
Essential role of Ca2+-binding protein 4, a Cav1.4 channel regulator, in photoreceptor synaptic function
PMID: 15452577
Gene: CABP4
HGNC: 1386
Disease: cone-rod synaptic disorder, congenital nonprogressive
MONDO: 0012490
InheritancePattern: autosomal recessive
Prevalence: The prevalence of the Åland eye disease or incomplete congenital stationary night blindness phenotype was estimated at 1 in 22,000 based on a Danish male cohort, with CABP4 variants specifically responsible for 1 out of 35 cases (PMID: 28002560).
Penetrance: Penetrance appears to be 100% among the reported individuals harboring biallelic disease-causing CABP4 variants.
c.3454G>T;p.E1152*
Case#: Arno_2015_Family_GC19774_Patient_3, male, first seen at age 2 years, family origin not reported
CasePresentingHPOs: HP:0025313 (Exophoria), HP:0000545 (Myopia), HP:6001439 (Tigroid fundus), HP:0012795 (Abnormal optic disc morphology, specifically myopic discs), HP:0007663 (Reduced visual acuity), HP:0008323 (Abnormal light- and dark-adapted electroretinogram), HP:0030844 (Undetectable pattern electroretinogram)
CaseHPOFreeText: BCVA was 0.350 / 0.325 logMAR (Snellen 20/50 or 20/40). OCT showed loss of inner segment-ellipsoid over peripheral macular areas. Initial ERG showed rod more affected than cone. Later ERG showed more severe cone deterioration. Overall phenotype was summarized as "high myopia and retinal dystrophy in childhood with no significant fundus changes".
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous genotyping was by whole exome sequencing.
CaseMethod1: WES
CaseMethod2: Sanger sequencing of RBP3
CaseGenotypingMethod: Genotyping was performed by whole exome sequencing, followed by Sanger sequencing of RBP3.
Variant: The individual harbors the NM_002900.3(RBP3):c.1530T>A (p.Tyr510Ter) variant in the homozygous state.
CAID: CA376670175
gnomAD: The variant was not found in gnomAD version 4.1.1.
VariantEvidence: NM_002900.3(RBP3):c.1530T>A (p.Tyr510Ter) is a nonsense variant within exon 1 of 4 that is predicted to trigger nonsense-mediated decay.
CaseAddInfo: The proband comes from a consanguineous family with a similarly affected younger sibling sharing the same homozygous genotype.
CasePMIDs: N/A
c.1530T>A;p.Y510*
Case#: Arno_2015_Family_GC17452_Patient_2, female, first seen at age 4 years, family origin not reported
CasePresentingHPOs: HP:0011003 (High myopia), HP:0000662 (Nyctalopia), HP:0030534 (Abnormal best corrected visual acuity test), HP:6001439 (Tigroid fundus), HP:0030602 (Abnormal fundus autofluorescence imaging, specifically patchy increased FAF in the vascular arcades), HP:0030603 (Abnormal optical coherence tomography, specifically showing loss of inner segment-ellipsoid over peripheral macular areas), HP:0008275 (Abnormal light-adapted electroretinogram, specifically showing delay and amplitude reduction of cone responses)
CaseHPOFreeText: BCVA was 0.550 / 0.575 logMAR (Snellen 20/80). FAF showed increased signal in vascular arcades, OCT showed loss of inner segment-ellipsoid over peripheral macular areas, ERG showed delay and amplitude reduction of cone responses. Overall phenotype was summarized as "high myopia and retinal dystrophy in childhood with no significant fundus changes".
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous genotyping was by whole exome sequencing.
CaseMethod1: WES
CaseMethod2: Sanger sequencing of RBP3
CaseGenotypingMethod: Genotyping was performed by whole exome sequencing, followed by Sanger sequencing of RBP3.
Variant: The individual harbors the NM_002900.3(RBP3):c.3454G>T (p.Glu1152Ter) variant in the homozygous state.
CAID: CA376677245
gnomAD: The variant was not found in gnomAD version 4.1.1.
VariantEvidence: NM_002900.3(RBP3):c.3454G>T (p.Glu1152Ter) is a nonsense variant within exon 4 of 4 that is predicted not to trigger nonsense-mediated decay but rather to truncate the C-terminal 8% of the protein product.
CaseAddInfo: The proband comes from a consanguineous family with a similarly affected older sibling sharing the same homozygous genotype.
CasePMIDs: N/A
consanguineous families
FamilyLabel: Perrault_2000_Family_9
Family#PresentingHPOs: N/A
Family#PresentingHPOFreeText: Affected family members are described as having Leber congenital amaurosis.
FamilyNotHPOs: N/A
CountryOrigin: Algeria
Ethnicity: Arab
Race: Not described
Family#PreviousTesting: Linkage mapping of the disease locus to chromosome 17p13.1 (PMID: 7581387, PMID: 8641699)
Family#Method1: Sanger sequencing of PCR products from each of the 20 exons
Family#Method2: N/A
Family#GenotypingMethod: Family members were initially subjected to homozygosity mapping, establishing linkage to chromosome 17p13.1 and particularly between the D17S1353 and D17S1854 markers (PMID: 7581387, PMID: 8641699). Subsequent genotyping was performed by Sanger sequencing of PCR products from the GUCY2D locus.
Affected: 4
Unaffected: 2
Segregations: 3 segregations were reported, with none inconsistent with the proposed mechanism of inheritance (Figure 3a). The family is reportedly consanguineous.
PublishedLOD: N/A
eLOD: 2.06
AddSegregationInfo: N/A
ProbandLabel: Perrault_2000_Family_9_Proband
Variant: Affected individuals are homozygous for the NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) variant.
ClinVar: 9350
gnomAD: The variant exhibits a maximum allele frequency of 0.000008790 in gnomAD version 2.1.1 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7912849-T-C?dataset=gnomad_r2_1
FamilyAddInfo: N/A
FamilyPMIDs: PMID: 7581387, PMID: 8641699
F589S
Case#: Perrault_2000_Family_11_Proband, FEmale, age unknown, family origin in Algeria with Arab ancestry
CasePresentingHPOs: N/A
CaseHPOFreeText: The individual is described as having Leber congenital amaurosis.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Linkage mapping of the disease locus to chromosome 17p13.1 (PMID: 7581387, PMID: 8641699)
CaseMethod1: Sanger sequencing of PCR products from each of the 20 exons
CaseMethod2: N/A
CaseGenotypingMethod: The individual was included in multi-family homozygosity mapping, establishing linkage to chromosome 17p13.1 and particularly between the D17S1353 and D17S1854 markers (PMID: 7581387, PMID: 8641699). Subsequent genotyping was performed by Sanger sequencing of PCR products from the GUCY2D locus.
Variant: The individual is homozygous for the NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) variant.
ClinVar: 9350
gnomAD: The variant exhibits a maximum allele frequency of 0.000008790 in gnomAD version 2.1.1 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7912849-T-C?dataset=gnomad_r2_1
VariantEvidence: The evidence supporting the pathogenicity of the variant is limited to computational prediction alone.
CaseAddInfo: The family is reportedly consanguineous.
CasePMIDs: PMID: 7581387, PMID: 8641699
Identification of a Novel Bardet-Biedl Syndrome Protein, BBS7, That Shares Structural Features with BBS1 and BBS2
PMID: 12567324
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 sole affected individual, –05, in consanguineous family KK26 harbors a homozygous 4-bp deletion in exon 7 that is predicted to lead to premature termination in exon 9 (K237fsX296), thereby abolishing ∼64% of the wild-type protein.
Case#: Badano_2003_Family_KK26_Proband_05, gender, age, and origin not reported.
CasePresentingHPOs: N/A
CaseHPOFreeText: The patient has been diagnosed with Bardet-Biedl syndrome. Specific phenotypes have not been described in detail.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous genotyping consisted of linkage mapping using a 10-cM linkage map set to identify regions of homozygosity unique to the affected family member only.
CaseMethod1: Homozygosity analysis
CaseMethod2: Sanger sequencing of the BBS7 locus
CaseGenotypingMethod: Genotyping first identify regions of homozygosity unique to the affected family member, then performed Sanger sequencing of the BBS7 locus.
Variant: The patient harbors the NM_176824.3(BBS7):c.709_712del (p.Lys237fs) variant in the homozygous state.
ClinVar ID: 3017
gnomAD: The NM_176824.3(BBS7):c.709_712del (p.Lys237fs) variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_176824.3(BBS7):c.709_712del (p.Lys237fs) is an out-of-frame deletion variant in exon 7 of 18 and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 67% of the protein product.
CaseAddInfo: The proband is a member of family KK26, which is known to be consanguineous. The proband has two unaffected carrier parents, 5 unaffected carrier siblings, and 1 unaffected non-carrier sibling.
CasePMIDs: N/A
Monoclonal antibodies were used with Western blot analysis to localize the wild-type mouse peripherin/rds protein to isolated mouse rod outer segments and to show that it, like bovine peripherin, exists as two subunits linked by one or more disulfide bonds.
Selection A- Gene is expressed in tissues relevant to disease:
ExperimentName: Wild-type Prph2 localizes to mouse rod outer segments.
TissueExpression: photoreceptor outer segment layer (UBERON:0003926)
ExpressionEvidence: Western blotting with an anti-Prph2 antibody confirms that Prph2 is present in retinal outer segments and exists a a dimer (Fig. 2), although other control tissues are absent.
The ability of Nr2e3 to rescue retinal degeneration before disease onset was tested by subretinal delivery of AAV8-Nr2e3 in five mouse models of RP. All models except rd1 were injected at P0 and evaluated at 3–4 months of age. rd1 animals were injected at P0 and evaluated at 1 month of age due to their accelerated rate of disease progression. Although not all models have a clinical phenotype, considerable improvements were observed in the fundus of RhoP23H, rd16, and rd7 mice (Fig. 3). Interestingly, we observed the rd16 mice have a red fundus with increased and pronounced vessels (not previously reported). While no vascular leakage has been observed in rd16 mice when examined by fluorescein angiography (our unpublished data), the fundus observation resolves with Nr2e3 administration. Improvement was observed in the rd7 phenotype, with reduction of retinal spots in AAV8-Nr2e3 treated eyes compared with untreated eyes at 3 months post injection.
ExperimentName: AAV8-Nr2e3 rescue of rd7/rd7 mice
RescueModel: Mus musculus
GeneAlteration: Rescue was performed by subretinal injection of AAV8-Nr2e3 (or no treatment) into rd7/rd7 mice with homozygous disruption of endogenous Nr2e3
RescueVariant: No variant form of Nr2e3 was studied in this rescue experiment.
RescuePhenotype: The rescued phenotype is retinal spots in the fundus (Figure 3).
RescueMethod: This rescue model has introduction of the virally packaged mouse wild-type Nr2e3 gene.
RescueEvidence: Subretinal administration of the gene results in considerable improvement of the retinal spots in the fundus compared with untreated eyes 3 months post-injection (Figure 3).
ModelVariant: The model harbors homozygous out-of-frame deletion of 380 bp within the coding region of Nr2e3.
Osteoporosis Pseudoglioma Syndrome
PMID: 33531964
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.
Identification of three novel OA1 gene mutations identified in three families misdiagnosed with congenital nystagmus and carrier status determination by real-time quantitative PCR assay
PMID: 12515581
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.
However, sequencing of KCNJ13 (genomic accession CH471063, mRNA-NM_002242) showed a heterozygous c.484C > T transition, changing a CGG codon to TGG and resulting in an R162W change in the amino acid sequence (Figure 1A). This sequence change is present in all affected individuals in the family and not present in unaffected family members or 210 unrelated ethnically matched control individuals (420 chromosomes, providing a power of more than 95% to detect a polymorphism with a frequency of 0.01).
Case#: Hejtmancik_2008_Family_55001_Proband, sex and age not specified, family origin described as American of European ancestry
CasePresentingHPOs: Snowflake vitreoretinal degeneration HP:0011533, Corneal guttata HP:0012038, Presenile cataracts HP:0007819, Abnormal vitreous humor morphology HP:0004327, Retinal detachment HP:0000541
CaseHPOFreeText: All family members have been diagnosed with Snowflake vitreoretinal degeneration between the ages of 12 and 85 years of age. Please note that detailed phenotypes were found in PMID: 14644728, and included fibrillar vitreous degeneration.
CaseNotHPOs: N/A
CaseNotHPOFreeText: Orofacial features, early-onset hearing loss, and arthritis were absent.
CasePreviousTesting: The proband was previously subjected to linkage analysis mapping the causal locus to chromosome 2 (PMID: 15557460).
CaseMethod1: linkage analysis
CaseMethod2: Sanger sequencing of KCNJ13, COL4A3, SLC19A3, DNER, SLC17, 16A14, LOC646839, CAB39, PSMD1, ARMC9, NCL, PTMA, PDE6D, COPS7B, ECEL1, EFHD1, TNRC15, ATG16L1, SAG, USP40, and CENTG2
CaseGenotypingMethod: The family was previously genotyped by linkage analysis mapping the causal locus to chromosome 2 (PMID: 15557460), followed by Sanger sequencing of KCNJ13, COL4A3, SLC19A3, DNER, SLC17, 16A14, LOC646839, CAB39, PSMD1, ARMC9, NCL, PTMA, PDE6D, COPS7B, ECEL1, EFHD1, TNRC15, ATG16L1, SAG, USP40, and CENTG2.
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 (Figure 2).
CaseAddInfo: The proband's family includes 12 other affected individuals carrying the variant, and 14 unaffected individuals (as well as 4 unaffected spouses) without the variant.
CasePMIDs: PMID: 15557460, PMID: 14644728
Phenotype in retinol deficiency due to a hereditary defect in retinol binding protein synthesis
PMID: 9888420
Gene: RBP4
HGNC: 9922
Disease: progressive retinal dystrophy due to retinol transport defect
MONDO: 0014060
InheritancePattern: autosomal recessive
Prevalence: RBP4-related cases have an estimated prevalence of less than 1 in 1,000,000 (https://www.orpha.net/en/disease/detail/352718?search=&mode=name)
Penetrance: RBP4 disease-causing variants appear to have complete penetrance in biallelic cases.
Abnormal Vessel Formation in the Choroid of Mice Lacking Tissue Inhibitor of Metalloprotease-3
PMID: 18408187
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
As previously reported, photoreceptors in the XLPRA1 retina developed and functioned normally (17). Retinal function remained normal until 6 months of age or later, after which there was a decrease in the amplitude of the dark-adapted rod and cone responses (Fig. 4IA1–3). Morphologically, XLPRA1 photoreceptors remained normal until young adulthood; thereafter, rods showed distinct irregularities of the outer segments, followed by degeneration. Cone abnormalities appeared less severe, and a proportionally larger number of cones remained in the visual cell layer in late disease (Fig. 4IIA–D). All affected males showed end-stage retinal disease by 4 years of age.In contrast, retinal development is aberrant in XLPRA2. ERG abnormalities were evident by 5–6 weeks of age; the responses were low in amplitude, abnormal in waveform, and deteriorated with age (Fig. 4IB1–3). There was relative preservation of cone flicker responses when rod function is severely compromised, but the cone signals are abnormally small and, in older animals, increased in timing. In parallel, photoreceptor morphogenesis is abnormal. Outer segments are highly disorganized and disoriented as they develop (Fig. 4IIE), and visual cell degeneration is present by 4 months and progresses (Fig. 4IIF,G). By 2 years, end-stage degeneration is present in all affected animals (Fig. 4IIH). Cone abnormalities were less severe, and a proportionally larger number of cones remained late in the disease.In heterozygotes, the retinal functional abnormalities reflected the underlying photoreceptor pathology. Low-amplitude responses were present in young adult carriers of either genotype (Fig. 4IC–E), but progressive loss of function was found only in XLPRA2 (data not shown). Other than foci of patchy retinal degeneration, the remaining photoreceptors in XLPRA1 heterozygotes were normal (Fig. 4III). This was not the case for XLPRA2, since the carrier retina failed to develop normally, and surviving photoreceptors showed severe structural abnormalities (compare Fig. 4III with J and K). Such severe pathology in XLPRA2 carriers indicates that the mutation kills mutant photoreceptors early in development, and produces collateral damage in surviving normal ones.
ExperimentName: Two dog models of Rpgr loss-of-function
NonHumanModel: Canis lupus familiaris
GeneAlteration: The two models have disruption of the dog Rpgr gene by the c.1028_1032del frameshift variant or the c.1084_1085del frameshift variant, respectively.
ModelPhenotype: Normal photoreceptors until young adulthood in one model, HP:0000546 (Retinal degeneration), Photoreceptor outer segment cell degeneration, HP:0030483 (Reduced amplitude of dark-adapted bright flash electroretinogram a-wave), HP:0008275 (Abnormal light-adapted electroretinogram), relative sparing of cones in both models, HP:0000618 (Blindness)
HumanPhenotype: HP:0007642 (Congenital stationary night blindness), HP:0007994 (Peripheral visual field loss), HP:0000529 (Progressive visual loss), HP:0000365 (Hearing impairment), HP:0002205 (Recurrent respiratory infections), HP:0011109 (Chronic sinusitis), HP:0000388 (Otitis media), HP:0002837 (Recurrent bronchitis), HP:0012263 (Immotile cilia), HP:0005938 (Abnormal respiratory motile cilium morphology)
ModelEvidence: The two models have been well-characterized at the ocular level and exhibit ERG abnormalities (Fig. 4IB1-3) and degeneration of visual cells and outer segment disorganization, leading to end-stage retinal disease (Fig.4IIE-4IIH). These phenotypes are consistent with human patient features such as night blindness, central visual field loss, and peripheral visual field loss.
ModelVariant: The models study naturally occurring variants that do not have equivalent / orthologous variants reported in human patients.
First, we identified the uncloned osm-12(n1606) allele as a candidate bbs-7 mutant on the basis that the bbs-7 gene lies within the osm-12 critical interval, that bbs-7 contains an X box in its promoter (Ansley et al. 2003), and the fact that the osmolarity avoidance (Osm) phenotype is characteristic of ciliary defects in C. elegans (Perkins et al. 1986). Sequencing of the bbs-7 gene from osm-12(n1606) mutant animals revealed a G→A nonsense mutation at nucleotide 2899 (Fig. 2A,C). The n1606 allele is likely to be null, as it contains a stop codon after only 32% of the coding region (henceforth, for simplicity, we often refer to the osm-12(n1606) mutant as the bbs-7 gene mutant).
ExperimentName: Naturally occurring bbs-7 loss-of-function C. elegans model
NonHumanModel: C. elegans
GeneAlteration: The model animals harbor a naturally occurring homozygous nonsense variant at nucleotide 2899 within the bbs-7 locus.
ModelPhenotype: short cilia, defective chemotaxis, defective intraflagellar transport, IFT mislocalization
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 naturally occurring C. elegans model of biallelic bbs-7 disruption. The mutant animals exhibit reduced chemotaxis (dependent on two chemosensory neurons, Figure 2E), shorter cilia (Figure 3), defective localization of IFT particles (Figure 4), and reduced intraflagellar transport (Figure 5). Rescue of chemotaxis with expression of the wild-type C. elegans bbs-7 gene directly linked the defect with bbs-7 (Figure 2E).
ModelVariant: This model did not introduce a disease-associated variant known from an affected human patient, but rather studied a naturally occurring and apparent null variant disrupting bbs-7 expression.
Loss of C. elegans BBS-7 and BBS-8 protein function results in cilia defects and compromised intraflagellar transport
PMID: 15231740
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.
CSNB1 in Chinese families associated with novel mutations in NYX
PMID: 16670814
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.
Two-year progression analysis of RPE65 autosomal dominant retinitis pigmentosa
PMID: 29947567
Gene: RPE65
HGNC: 10294
Disease: Retinitis pigmentosa 87 with choroidal involvement
MONDO: 0032873
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 8,000 and 1 in 27,000). The prevalence of Retinitis pigmentosa 87 with choroidal involvement is considered to be much lower.
Penetrance: Incomplete penetrance, estimated at 80%
Family members V.5, V.6, VI.5, and VI.6 have previously been shown to carry a heterozygous c.545A>G (p.Tyr182Cys) mutation in exon 5 of the TIMP3 gene, but detailed phenotyping was not reported.
FamilyLabel: Gliem_2015_Family_2
Family#PresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0011510 (Drusen), HP:0000533 (Chorioretinal atrophy), HP:0011506 (Choroidal neovascularization)
FamilyHPOFreeText: Onset of symptoms in the early fifth or sixth decade of life, with either dark adaptation problems, metamorphopsia, or visual loss being the first symptoms, central and midperipheral atrophy, central fibrosis. Some affected family members were largely asymptomatic into the 6th decade of life, but had central retinal drusen. Choroidal neovascularization was observed in some family members and appeared to be a driver of vision loss.
FamilyNotHPOs: HP:0000662 (Nyctalopia)
FamilyNotHPOFreeText: Dark adaptation problems, early onset of symptoms
CountryOrigin: Germany
Family#PreviousTesting: N/A
Family#GenotypingMethod: Sanger sequencing of PCR products from all 5 exons and flanking splice junctions of the TIMP3 gene.
Affected: 6
Unaffected: 2
Segregations: 12
PublishedLOD: N/A
eLOD: 2.1
AddSegregationInfo: N/A
ProbandLabel: Gliem_2000_Family_2_patient_V.1
Variant: Patients harbor the NM_000362.5(TIMP3):c.545A>G (p.Tyr182Cys) missense variant.
CAID: CA411540365
gnomAD: Variant is absent from gnomAD.
FamilyAddInfo: Some of the family members were previously identified by genotyping as having Sorsby fundus dystrophy (PMID:25390527), and are more extensively phenotypically described in this study.
FamilyPMIDs: PMID:25390527
III.5
Case: Gliem_2000_Family_3_patient_III.5, male, country of origin Germany, onset at 31 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), HP:0007737 (Bone spicule pigmentation of the retina),
CaseHPOFreeText: Relatively early presentation at age 31 with nyctalopia and prolonged dark adaptation. Evaluation at age 56 showed widespread central and peripheral atrophy, central fibrosis, and reduced choroidal thickness.
CaseNOTHPOs: N/A
CaseNOTHPOFreeText: N/A
CasePreviousTesting: Targeted next-generation sequencing of the proband (for a 74-gene panel of retinal dystrophy genes), identifying the TIMP3 variant as well as a heterozygous c.1107G>A (p.Trp369) variant in RP1L1*
GenotypingMethod: Sanger sequencing of PCR products from the TIMP3 and RP1L1 genes
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: Patients harbor the NM_000362.5(TIMP3):c.452A>G (p.Tyr151Cys) missense variant.
CAID: CA411540149
gnomAD: Variant is absent from gnomAD.
VariantEvidence: This missense variant within exon 5 of TIMP3 results in an unpaired Cys residue.
single base pair substitution in the splice acceptor site; IVS10-2A->G
Case#: Riazuddin_2006_61074_patient_10, male, age 25 years at time of study, Pakistani family origin from remote Punjab province
CasePresentingHPOs: HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007737 (Bone spicule pigmentation of the retina), HP:0000550 (Undetectable electroretinogram)
CaseHPOFreeText: The proband and her affected family members have been diagnosed with autosomal recessive retinitis pigmentosa.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Genome-wide linkage analysis, with maximum LOD score associated with the D5S2015 microsatellite marker on chromosome 5q31-33.
CaseMethod1: Genome-wide linkage analysis
CaseMethod2: Sanger sequencing of the candidate gene PDE6A
CaseGenotypingMethod: Genome-wide linkage analysis was initially performed on multiple families, with maximum LOD score associated with the D5S2015 microsatellite marker on chromosome 5q31-33. Sanger sequencing was then performed on PCR products of exons and flanking regions from the PDE6A candidate locus.
Variant: The affected members of Family 61074 harbor the NM_000440.3(PDE6A):c.1408-2A>G variant in the homozygous state.
ClinVar: 225119
gnomAD: This variant is present in gnomAD v2.1.1 at a frequency of 0.00003266 (1/30616 with no homozygotes) in the South Asian population https://gnomad.broadinstitute.org/variant/5-149276341-T-C
VariantEvidence: NM_000440.3(PDE6A):c.1408-2A>G is a variant disrupting a splice acceptor site in intron 10 that is predicted to result in exon 11 skipping, truncating 22 amino acids (~3%) of the protein product.
CaseAddInfo: The patient is from a family with consanguineous unions.
CasePMIDs: N/A
In our study, a patient from arRP family 4263 was identified to carry a novel homozygous nonsense variant, 1786C>T:p.(R596*), in ADAM9 ({"type":"entrez-nucleotide","attrs":{"text":"NM_003816.2","term_id":"54292119","term_text":"NM_003816.2"}}NM_003816.2), which introduces a premature stop in exon16, resulting in a truncated protein or nonsense-mediated decay. A segregation test indicated that the nonsense variant cosegregated with the disease phenotype (Fig. 5C). To clarify the ambiguity between the molecular and clinical diagnosis, we reevaluated the clinical information for this patient. Patient 4263_1 was a 9-year-old boy from a consanguineous family. Initially, he experienced severe night blindness but no significant loss in daylight vision. His vision acuity was 0.3/0.3 (decimal Snellen) at first clinical visit and decreased rapidly to 0.08/0.1 (decimal Snellen). Full-field ERG showed both rod and cone functions were impaired. However, the amplitude of b-wave in dark-adapted rod response was more severely decreased compared with cone responses. Fundus image and OCT are shown in Supplementary Figure S3. Based on these clinical phenotypes and the ADAM9 mutation identified in the family, the patients were rediagnosed to have CRD with early-onset retinal dystrophy.
Case#: Fu_2013_Patient_4263_1, male, age 9 at time of report, family origin reported to be Chinese
CasePresentingHPOs: HP:0030534 (Abnormal best corrected visual acuity test), HP:0000662 (Nyctalopia), HP:0007663 (Reduced visual acuity), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude), HP:0007984 (Electronegative electroretinogram), HP:0410280 (Pediatric onset)
CaseHPOFreeText: The proband was initially diagnosed with retinitis pigmentosa with an autosomal recessive pattern of inheritance, and subsequently re-diagnosed with cone-rod dystrophy with early-onset retinal dystrophy.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: The proband was initially genotyped by next-generation sequencing focusing on a panel of 163 known retinal disease genes.
CaseMethod1: Next-generation sequencing panel (163 genes)
CaseMethod2: Sanger sequencing of ADAM9
CaseGenotypingMethod: The proband was initially genotyped by next-generation sequencing focusing on a panel of 163 known retinal disease genes, followed by Sanger sequencing of ADAM9.
Variant: The proband harbors the NM_003816.3(ADAM9):c.1786C>T (p.Arg596Ter) variant in the homozygous state.
CAID: CA370746588
gnomAD: This variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_003816.3(ADAM9):c.1786C>T (p.Arg596Ter) is a nonsense variant in exon 16 of 21, which is predicted to trigger NMD or to truncate the C-terminal ~27% of the protein product.
CaseAddInfo: The proband's parents are consanguineous and are each heterozygous for the variant, while his unaffected sister does not carry the variant.
CasePMIDs: N/A
Functional photoreceptor loss revealed with adaptive optics: An alternate cause of color blindness
PMID: 15148406
Gene: OPN1LW
HGNC: 9936
Disease: protan color blindness
MONDO: 0010565
InheritancePattern: X-linked
Prevalence: The overall prevalence of protan color blindness is approximately 1% in males, which is higher than that of blue cone monochromacy (~1 in 100,000, PMID: 35759666).
Penetrance: Known disease-causing alleles appear to be almost completely penetrant in males (PMID: 21167193).
Deletion in the OA1 gene in a family with congenital X linked nystagmus
PMID: 11520764
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.
Interphotoreceptor matrix proteoglycans IMPG1 and IMPG2 proteolyze in the SEA domain and reveal localization mutual dependency
PMID: 36109576
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.
Patient 20955 received a diagnosis of LCA
Case#: Yzer_2006_Patient_20955, female, diagnosed in the weeks after birth, Dutch or Belgian family origin
CasePresentingHPOs: HP:0003593 (Infantile onset), HP:0000639 (Nystagmus), HP:0007663 (Reduced visual acuity), HP:0000563 (Keratoconus), HP:0001483 (Eye poking), HP:0008043 (Retinal arteriolar constriction), HP:0007814 (Retinal pigment epithelial mottling), HP:0007688 (Undetectable light- and dark-adapted electroretinogram)
CaseHPOFreeText: The individual is described as having Leber congenital amaurosis. Retinal pigment epithelium mottling in the mid- and far periphery was minimal.
CaseNotHPOs: HP:0000662 (Nyctalopia), HP:0000613 (Photophobia), HP:0001098 (Abnormal fundus morphology), HP:0000543 (Optic disc pallor), HP:0030825 (Absent foveal reflex)
CaseNotHPOFreeText: N/A
CasePreviousTesting: An LCA-specific microarray ChIP was used for initial genotyping, using antisense oligos to screen for 301 known disease-associated variants 6 LCA genes (AIPL1, CRB1, CRX, GUCY2D, RPE65, and RPGRIP1) and two early-onset RP genes (LRAT and MERTK).
CaseMethod1: Sanger sequencing of PCR products from the relevant exon of GUCY2D.
CaseMethod2: N/A
CaseGenotypingMethod: The individual was initially screened using an LCA-specific microarray ChIP with antisense oligos to detect 301 known disease-associated variants 6 LCA genes (AIPL1, CRB1, CRX, GUCY2D, RPE65, and RPGRIP1) and two early-onset RP genes (LRAT and MERTK). Subsequent genotyping was performed by Sanger sequencing of PCR products from the relevant exon of the GUCY2D locus.
Variant: The individual is homozygous for the NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant.
ClinVar: 98563
gnomAD: The NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant exhibits a maximum allele frequency of 0.0002943 in gnomAD version 2.1.1 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7917236-C-T
VariantEvidence: Multiple publications have found functional defects in the NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant. PMID: 25477517 shows defective binding to its interacting partner RD3, while PMID: 20050595 and PMID: 23035049 show reduced basal enzymatic activity and inability to interact with the activity-stimulating binding partner GCAP1.
CaseAddInfo: Parents were not reported to be consanguineous. Segregation / phasing of two variants was confirmed by parental genotyping.
CasePMIDs: N/A
Deletion of the Impg2 gene causes the degeneration of rod and cone cells in mice
PMID: 32242237
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.
A Novel Protein LZTFL1 Regulates Ciliary Trafficking of the BBSome and Smoothened
PMID: 22072986
Gene: BBS1
HGNC: 966
Disease: Bardet-Biedl syndrome 1
MONDO: 0008854
InheritancePattern: autosomal recessive
Prevalence: The prevalence of BBS1 variants among Bardet-Biedl syndrome cohorts has been reported as at least 20% (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.
CORD9 a New Locus for arCRD: Mapping to 8p11, Estimation of Frequency, Evaluation of a Candidate Gene
PMID: 11581183
Gene: ADAM9
HGNC: 216
Disease: cone-rod dystrophy 9
MONDO: MONDO:0013002
InheritancePattern: autosomal recessive
Prevalence: The prevalence of cone-rod dystrophy in general is estimated to be 1 in 40,000 (PMID: 17270046), however, the specific prevalence of cone-rod dystrophy 9 is unknown.
Penetrance: Penetrance appears to be complete in reported families, but it is possible that incomplete penetrance may be associated with some variants.
Identification of 11 Novel Mutations in 8 BBS Genes by High-Resolution Homozygosity Mapping
PMID: 19797195
Gene: BBS1
HGNC: 966
Disease: Bardet-Biedl syndrome 1
MONDO: 0008854
InheritancePattern: autosomal recessive
Prevalence: The prevalence of BBS1 variants among Bardet-Biedl syndrome cohorts has been reported as at least 20% (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.
c.2538G>C (p.K846N) in family MOL0430
Case#: Lazar_2014_Family_MOL0430_Patient_1, male, age 31 at time of report, national origin in Israel, ethnicity listed as North African Jewish
CasePresentingHPOs: HP:0410280 (Pediatric onset), HP:0030515 (Moderately reduced visual acuity), HP:0011003 (High myopia), HP:0030479 (Abnormal amplitude of light-adapted flicker electroretinogram), HP:0000613 (Photophobia), HP:0007703 (Abnormality of retinal pigmentation), HP:0008179 (Decreased Arden ratio of electrooculogram)
CaseHPOFreeText: The patient has been diagnosed with cone-rod dystrophy.
CaseNotHPOs: HP:0030480 (Abnormal timing of light-adapted flicker electroretinogram), HP:0030470 (Abnormal dark-adapted bright flash electroretinogram)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
CaseMethod1: Whole exome sequencing of the proband
CaseMethod2: Confirmation by Sanger sequencing
CaseGenotypingMethod: The proband was genotyped by whole exome sequencing, followed by confirmation by Sanger sequencing.
Variant: The proband harbors the NM_000180.4(GUCY2D):c.2538G>C (p.Lys846Asn) variant in the heterozygous state.
ClinVar: 812329
gnomAD: The variant was not found in gnomAD.
VariantEvidence: NM_000180.4(GUCY2D):c.2538G>C (p.Lys846Asn) is a missense variant located within the coiled-coil domain that mediates 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). Cases from this family may be less severely affected, possibly similar to a reported variant at codon 849 (PMID: 26298565).
CaseAddInfo: The proband is an isolated case without family member phenotypes and genotypes available.
CasePMIDs: N/A
compound heterozygous mutations in GUCY2D
Case#: Stunkel_2018_Patient_2, male, age 9 at diagnosis with congenital night blindness, age 14 at time of report, ethnic origin not mentioned
CasePresentingHPOs: HP:0003621 (Juvenile onset), HP:0000662 (Nyctalopia), HP:0030474 (Undetectable dark-adapted electroretinogram), HP:0007987 (Progressive visual field defects), HP:0001133 (Constriction of peripheral visual field), HP:0002527 (Falls), HP:0030329 (Retinal thinning)
CaseHPOFreeText: Minor color vision errors were detected by D15 testing.
CaseNotHPOs: HP:0003593 (Infantile onset), HP:0030534 (Abnormal best corrected visual acuity test), HP:0030586 (Abnormal Ishihara plate test), HP:0000539 (Abnormality of refraction), HP:0000639 (Nystagmus), HP:0000486 (Strabismus), HP:0007663 (Reduced visual acuity), HP:0030473 (Abnormal light-adapted flicker electroretinogram)
CaseNotHPOFreeText: N/A
CasePreviousTesting: Negative screening for variants in NYX, CACNA1F, RHO, or TRPM1
CaseMethod1: Whole exome sequencing
CaseMethod2: N/A
CaseGenotypingMethod: This individual was initially subjected to screening for variants in NYX, CACNA1F, RHO, or TRPM1, with negative results. Whole exome sequencing then detected 2 variants in GUCY2D.
Variant: The individual is compound heterozygous for the NM_000180.4(GUCY2D):c.247C>T (p.Arg83Cys) and NM_000180.4(GUCY2D):c.1633C>T (p.Gln545Ter) variants.
CAID: CA397943039
ClinVar: 689384
gnomAD: Neither variant was found in gnomAD.
VariantEvidence: Evidence supporting the pathogenicity of the NM_000180.4(GUCY2D):c.247C>T (p.Arg83Cys) variant is limited to computational prediction. NM_000180.4(GUCY2D):c.1633C>T (p.Gln545Ter) is a nonsense variant in exon 7 predicted to trigger NMD or to at least disrupt ~51% of the protein product through truncation.
CaseAddInfo: The mother of Patient 2 has been found to carry one of the variants in a heterozygous state, consistent with the expected segregation pattern.
CasePMIDs: N/A
Monoallelic IFT140 pathogenic variants are an important cause of the autosomal dominant polycystic kidney-spectrum phenotype
PMID: 26216056
Gene: IFT140
HGNC: 29077
Disease: polycystic kidney disease
MONDO: 0020642
InheritancePattern: autosomal dominant
Prevalence: The overall prevalence of polycystic kidney disease is between 1 in 400 and 1 in 1,000 individuals (PMID: 30523303).
Penetrance: Disease caused by monoallelic IFT140 variants is incompletely penetrant.
Here, we report that a mutation in the gene encoding a central effector of the phototransduction cascade, cGMP phosphodiesterase 6alpha'-subunit (PDE6alpha'), affects not only the vision but also the survival of cone photoreceptors in zebrafish. We isolated a zebrafish mutant, called eclipse (els), which shows no visual behavior such as optokinetic response (OKR). The cloning of the els mutant gene revealed that a missense mutation occurred in the pde6alpha' gene, resulting in a change in a conserved amino acid. The PDE6 expressed in rod photoreceptors is a heterotetramer comprising two closely related similar hydrolytic alpha and beta subunits and two identical inhibitory gamma subunits, while the PDE6 expressed in cone photoreceptors consists of two homodimers of alpha' subunits, each with gamma subunits. The els mutant displays no visual response to bright light, where cones are active, but shows relatively normal OKR to dim light, where only rods function, suggesting that only the cone-specific phototransduction pathway is disrupted in the els mutant. Furthermore, in the els mutant, cones are selectively eliminated but rods are retained at the adult stage, suggesting that cones undergo a progressive degeneration in the els mutant retinas. Taken together, these data suggest that PDE6alpha' activity is important for the survival of cones in zebrafish.
ExperimentName: The eclipse / els zebrafish mutant harbors a missense variant in the PDE6C ortholog pde6alpha'.
NonHumanModel: Danio rerio
GeneAlteration: The model animals are homozygous for a missense variant p.Met175Arg.
ModelPhenotype: HP:0008020 (cone dystrophy), HP:0030465 (Undetectable light-adapted electroretinogram), normal dark-adapted ERG, rapid and progressive elimination of cone photoreceptors from adult retinas
HumanPhenotype: HP:0030465 (Undetectable light-adapted electroretinogram), HP:0030534 (Abnormal best corrected visual acuity test), HP:0000551 (Color vision defect), HP:0000613 (Photophobia), HP:0000639 (Nystagmus), HP:0007401 (Macular atrophy), HP:0000545 (Myopia)
ModelEvidence: This is a naturally occurring zebrafish model that matches the mode of inheritance from the human patients and exhibits lack of light-adapted ERG responses (Figures 1K, 1M) and normal dark-adapted ERG responses. Optokinetic responses mediated by rod function were normal, while those mediated by cone function were absent (Figure 4). The mice also exhibit rapid and progressive loss of cone photoreceptors from retinal sections (Figures 1G, 1I) and abnormal shape of the photoreceptor outer segment (Figure 1C). Rod markers are maintained while cone markers are absent from adult animals (Figure 4).
ModelVariant: This model did not introduce a disease-associated variant known from an affected human patient, but rather studied a naturally occurring variant disrupting the PDE6alpha' locus orthologous to human PDE6C.
A CLN5 mutation causing an atypical neuronal ceroid lipofuscinosis of juvenile onset
PMID: 15728307
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
Pineal Photoreceptor Cells Are Required for Maintainingthe Circadian Rhythms of Behavioral Visual Sensitivity inZebrafish
PMID: 22815753
GeneName: GNAT2
HGNC: 4394
Disease: achromatopsia 4
MonDO ID: MONDO_0013465
Inheritance: autosomal recessive
RPGR Isoforms in Photoreceptor Connecting Cilia and the Transitional Zone of Motile Cilia
PMID: 12766038
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.
Both ROM-1 and RDS localize properly to the rim regions of OS discs in the WT, rdsY/+ and the rdsY/Y(arrows).
Wild-type Prph2 (referred to as RDS) co-localizes with ROM-1 protein within the rim regions of outer segment discs.
Mutations in the human retinal degeneration slow gene in autosomal dominant retinitis pigmentosa
PMID: 1684223
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).
In the second Afghan family, two children developed symptoms of a late infantile NCL. The mutation c.1137G>T (p.Trp379Cys) in CLN5 was identified.
FamilyLabel: Lebrun_2009_Family_2
Family#PresentingHPOs: HP:0001251 (Ataxia), HP:0001250 (Seizure), HP:0000750 (Delayed speech and language development), HP:0011463 (Childhood onset),
Family#PresentingHPOFreeText: Ataxia and delay in speech development were the first presenting phenotypes, with onset between ages 2 and 3. Epileptic seizures first occurred at age 4.
FamilyNotHPOs: N/A
FamilyNotHPOFreeText: N/A
CountryOrigin: N/A
Ethnicity: Family is of Afghan ethnic origin.
Race: N/A
Family#PreviousTesting: The extent of previous testing within this family is unclear.
Family#Method1: N/A
Family#Method2: N/A
Family#GenotypingMethod: CLN5 mRNA was reverse transcribed, PCR-amplified, and subjected to Sanger sequencing. This process was performed for both affected and control individuals (parents).
Affected: 2
Unaffected: 2
Segregations: 1 segregation is reported in the family.
PublishedLOD: N/A
eLOD: N/A
AddSegregationInfo: N/A
ProbandLabel: Lebrun_2009_Patient_2
Variant: Both affected patients are 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
FamilyAddInfo: The family is consanguineous, as parents are described as first degree cousins. Parents were heterozygous for the variant. Family relationships between individuals were verified.
FamilyPMIDs: N/A
De novo and inherited dominant variants in U4 and U6 snRNA genes cause retinitis pigmentosa
PMID: 41513982
Gene: RNU4-2
HGNC: 10193
Disease: inherited retinal dystrophy
MONDO: 0019118
InheritancePattern: autosomal dominant
Prevalence: The prevelance of retinitis pigmentosa in general is between 1 in 750 and 1 in 9,000 individuals (PMID: 37108642). The proportion of those cases caused by RNU4-2 variants is not well known.
Penetrance: Penetrance appears to be incomplete, with family pedigrees including apparently unaffected carriers.
Sorsby's fundus dystrophy mutations impair turnover of TIMP-3 by retinal pigment epithelial cells
PMID: 16223891
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
Members of a large French family (MTP327) were identified as having autosomal-dominant VMD. The disease was assessed with visual-acuity testing, funduscopy, and autofluorescence imaging. A full-fields electroretinogram (ERG) was recorded with a ganzfeld apparatus (Metrovision, Pérenchies, France) with a bipolar contact lens electrode on maximally dilated pupils according to the international ISCEV protocol. Dim blue stimulation after 20 min of dark adaptation was used for eliciting rod responses, and 30 Hz flicker stimulation after 10 min of light adaptation was used for eliciting cone responses. Electrooculography (EOG) was also performed, and the Arden ratio, defined as the ratio of the amplitude of the light peak over that of the dark trough, was calculated (normal value ≥ 1.80). There were eight affected individuals in six generations examined (Figure 1A). The age of onset ranged from 20 to 45 years, and the mean visual acuity was 20/30 (Table 1). Six of eight individuals had a single subfoveal vitelliform lesion, and two individuals, V:2 and V:5, had several small vitelliform deposits in both eyes (Figure 2). In most individuals, the ERG rod responses were above the lower limit (except IV:4, who had moderately decreased responses), and the cone responses were either normal or moderately decreased. All individuals except IV:6 had a normal or a slightly decreased (V:5) EOG Arden ratio (Table 1).
FamilyLabel: Manes_2013_Family_MTP327
Family#PresentingHPOs: HP:0007677 (Vitelliform-like macular lesions), HP:0030469 (Abnormal dark-adapted electroretinogram, specifically reduced)
FamilyPresentingHPOFreeText: The affected family members have been diagnosed with vitelliform macular dystrophy.
FamilyNotHPOs: N/A
FamilyNotHPOFreeText: N/A
CountryOrigin: The family is reportedly French.
Ethnicity: Not specifically described
Race: Not specifically described
Family#PreviousTesting: Previous genotyping included Sanger sequencing of BEST1 and PRPH2, followed by genome-wide scan using a 250K SNP Affymetrix array, which identified a shared 95.2 Mb haplotype on chromosome 6p12.1-q24.3 (encompassing 705 genes) in all affected family members. The candidate loci ELOVL4 and MCDR1 were then subjected to Sanger sequencing.
Family#Method1: Whole-exome sequencing of seven affected family members
Family#Method2: Sanger sequencing of IMPG1 to confirm the presence of the variant.
Family#GenotypingMethod: Whole-exome sequencing of seven affected family members was performed, followed by Sanger sequencing of IMPG1 to confirm the presence of the variant.
Affected: 8 genotyped
Unaffected: 4 genotyped
Segregations: 11 segregations are shown by the pedigree in Figure 1A.
PublishedLOD: 3.02 (for the D6S1622 marker on chromosome 6q13)
eLOD: N/A
AddSegregationInfo: All genotype-positive individuals were phenotype-positive in this family.
ProbandLabel: Manes_2013_Family_MTP327_Proband
Variant: The affected family members harbor the NM_001563.4(IMPG1):c.713T>G (p.Leu238Arg) variant in the heterozygous state.
ClinVar ID: 162133
gnomAD: This variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_001563.4(IMPG1):c.713T>G (p.Leu238Arg) is a missense site variant lacking evidence of a deleterious impact on the gene product.
FamilyAddInfo: The family's national origin has been reported as French. Age of onset ranged from 20 to 45 years.
FamilyPMIDs: N/A
To test the binding between SOST and LRP5 as well as LRP6, we produced CM containing a SOST-IgG fusion protein, which tags SOST with the constant region of immunoglobulin heavy chain, and the extracellular portion of LRP5 and LRP6 tagged with the Myc epitope (LRP5N-Myc and LRP6N-Myc). We found that SOST showed specific interactions with LRP5 and LRP6 but not with a similarly tagged low-density lipoprotein receptor (LDLRN-Myc) (Fig. 3A). Furthermore, when LDLRN-Myc was mixed in large excess together with LRP5N-Myc and LRP6N-Myc, SOST specifically bound to LRP5 and LRP6 (Fig. 3A). As an additional control for the binding specificity, we used Fz8CRD-IgG, which has a similar molecular mass to that of SOST-IgG. Despite much higher abundance in the CM, Fz8CRD-IgG was unable to precipitate any detectable amount of LRP5 or LRP6 protein (Fig. 3A).
ExperimentName: LRP5 interacts with SOST
InteractingGene: SOST (HGNC:13771)
InteractionType: Physical
InteractionMethod: Co-immunoprecipitation
InteractionEvidence: Immunoprecipitation of an exogenously expressed IgG-SOST fusion protein from conditioned medium pulled down the Myc-tagged soluble portion of LRP5 (and LRP6, but not control targets) (Fig. 3A). Subsequent experiments identified SOST as an LRP5/6 antagonist that attenuates canonical Wnt signaling through these receptors (Figure 4).
Mutations in the Genes for Interphotoreceptor Matrix Proteoglycans, IMPG1 and IMPG2, in Patients with Vitelliform Macular Lesions
PMID: 28644393
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.
IMPG2
Case#: van_Huet_2014_Patient_H-II:6, female, age 17 years at time of onset, age 46 years at the time of report, national origin reported as Dutch
CasePresentingHPOs: Nyctalopia HP:0000662, HP:0011462 (Young adult onset), HP:0000545 (Myopia), HP:0007663 (Reduced visual acuity), HP:0000518 (Cataract), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007737 (Bone spicule pigmentation of the retina), HP:0000550 (Undetectable electroretinogram), HP:0011510 (Drusen)
CaseHPOFreeText: The patient and her family members have been diagnosed with retinitis pigmentosa, with macular abnormalities present in all cases.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous genotyping consisted of autozygosity mapping (PMID: 20673862).
CaseMethod1: Homozygosity mapping
CaseMethod2: Sanger sequencing of the 19 exons of the IMPG2 gene
CaseGenotypingMethod: Genotyping consisted of autozygosity mapping (PMID: 20673862) followed by Sanger sequencing of the 19 exons of the IMPG2 gene.
Variant: The affected family members harbor the NM_016247.4(IMPG2):c.513T>G (p.Tyr171Ter) and NM_016247.4(IMPG2):c.2716C>T (p.Arg906Ter) variants in the compound heterozygous state.
ClinVar: 191181, 3548
gnomAD: These two variants were not found in gnomAD v2.1.1.
VariantEvidence: The NM_016247.4(IMPG2):c.513T>G (p.Tyr171Ter) variant is a nonsense variant in exon 4 of 19 that is predicted to lead to nonsense mediated decay or at least to C-terminal truncation of 86% of the protein product. The NM_016247.4(IMPG2):c.2716C>T (p.Arg906Ter) 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 27% of the protein product.
CaseAddInfo: The family is reportedly non-consanguineous, and the patient has a similarly affected sister with the same genotype. Segregation of the two variants has been demonstrated within the family.
CasePMIDs: PMID: 20673862
The 21-kDa protein is a transformation-sensitive metalloproteinase inhibitor of chicken fibroblasts
PMID: 1845973
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 NYX, encoding the leucine-rich proteoglycan nyctalopin, cause X-linked complete congenital stationary night blindness
PMID: 11062471
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.
Mutations in the X-Linked Retinitis Pigmentosa Genes RPGR and RP2 Found in 8.5% of Families with a Provisional Diagnosis of Autosomal Dominant Retinitis Pigmentosa
PMID: 23372056
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.
Members of a family with three living generations presented with mild loss of central vision in their 30s and 40s. Color vision was normal in the early stages, there was no photophobia, and on examination, no temporal pallor of the optic disc. Fluorescein angiography demonstrated small areas of parafoveal retinal pigment epithelium atrophy in the second generation and also RPE pigment clumping. However, there was no evidence of a bull's eye maculopathy on angiography. Subsequently a large macular area of well circumscribed atrophy of the RPE, choriocapillaris and neural retina developed and enlarged over time
Case#: Hughes_2012_CACD_Family_Proband, male, age not specified, origin listed as Northern Irish
CasePresentingHPOs: HP:0003581 (Adult onset), HP:0032037 (Mildly reduced visual acuity), HP:0007722 (Retinal pigment epithelial atrophy), HP:0000580 (Pigmentary retinopathy), HP:0030491 (Choriocapillaris atrophy), HP:0001105 (Retinal atrophy)
CaseHPOFreeText: The patient has been diagnosed with central areolar choroidal dystrophy. Onset was during the 30s or 40s, and the presenting symptom was mild loss of central vision.
CaseNotHPOs: HP:0000613 (Photophobia), HP:0000551 (Color vision defect), HP:0012511 (Temporal optic disc pallor)
CaseNotHPOFreeText: N/A
CasePreviousTesting: Linkage analysis previously mapped the disease-causing variant to chr17p13 (PMID: 9733038, PMID: 8733141).
CaseMethod1: Custom sequence capture array (next-generation) focusing on the linkage region on chromosome 17p13 (146 genes), using DNA from the proband and pooled affected and control samples.
CaseMethod2: Confirmation by Sanger sequencing of exon 15.
CaseGenotypingMethod: The proband and family members were genotyped by a combination of linkage analysis within the large pedigree, custom sequence capture array focusing on 146 genes within the linkage region on chromosome 17p13, and Sanger-based confirmation within exon 15.
Variant: The proband harbors the NM_000180.4(GUCY2D):c.2798T>C (p.Val933Ala) variant in the heterozygous state.
ClinVar: 617917
gnomAD: The variant was not found in gnomAD.
VariantEvidence: NM_000180.4(GUCY2D):c.2798T>C (p.Val933Ala) is a missense variant located in exon 15, which is part of the catalytic domain rather than the coiled-coil domain that mediates dimerization. Other variants for this disease entity are located within the coiled-coil domain instead. Phenotypic differences between this case and those may reflect genotype-phenotype correlation or differences in mechanism.
CaseAddInfo: The proband is a member of a large family (from the second generation) with other affected genotype-positive members.
CasePMIDs: PMID: 9733038, PMID: 8733141
BBS7
Case#: Fattahi_2014_Patient_40302, male, age not specified, ethnicity reported as Fars, national origin reported as Iranian
CasePresentingHPOs: HP:0001513 (Obesity), HP:0000510 (Rod-cone dystrophy), HP:0000545 (Myopia), HP:0001161 (Hand polydactyly), HP:0001829 (Foot polydactyly), HP:0000077 (Abnormality of the kidney), HP:0000026 (Male hypogonadism), HP:0002463 (Language impairment), HP:0000639 (Nystagmus), HP:0001627 (Abnormal heart morphology), HP:0000708 (Atypical behavior), HP:0002251 (Aganglionic megacolon), HP:0001156 (Brachydactyly), HP:0001511 (Intrauterine growth retardation)
CaseHPOFreeText: The patient has been diagnosed with Bardet-Biedl syndrome and retinitis pigmentosa.
CaseNotHPOs: HP:0000518 (Cataract), HP:0000662 (Nyctalopia), HP:0000486 (Strabismus), HP:0001328 (Specific learning disability)
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous genotyping consisted of Sanger sequencing of the BBS1, BBS2, BBS10, BBS3, BBS4, BBS6, BBS9, and BBS12 genes.
CaseMethod1: Sanger sequencing of the BBS1, BBS2, BBS10, BBS3, BBS4, BBS6, BBS9, and BBS12 loci
CaseMethod2: Sanger sequencing of the BBS7 locus.
CaseGenotypingMethod: Genotyping was performed using Sanger sequencing of the BSB1, BBS2, BBS10, BBS3, BBS4, BBS6, BBS7, BBS9, and BBS12 genes.
Variant: The patient harbors the NM_018190.4:c.1342_1346del (p.Gln448Argfs*13) and NM_018190.4:c.1443T>A (p.Cys481Ter) variants in the compound heterozygous state.
CAID: CA2580617740, CA358058685
gnomAD: The NM_018190.4:c.1342_1346del (p.Gln448Argfs*13) and NM_018190.4:c.1443T>A (p.Cys481Ter) variants were not found in gnomAD v2.1.1.
VariantEvidence: NM_018190.4:c.1342_1346del (p.Gln448Argfs*13) is a frameshift variant in exon 13 of 18 that is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 37% of the protein product. NM_018190.4:c.1443T>A (p.Cys481Ter) is a nonsense variant in exon 14 of 18 that is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 33% of the protein product..
CaseAddInfo: Consanguinity is not present in the proband's family.
CasePMIDs: N/A
Tissue inhibitor of metalloproteinases-3 is a component of Bruch's membrane of the eye.
PMID: 9006347
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
Factors that Determine Ca2+ Sensitivity of Photoreceptor Guanylyl Cyclase. Kinetic Analysis of the Interaction between the Ca2+-Bound and the Ca2+-Free Guanylyl Cyclase Activating Proteins (GCAPs) and Recombinant Photoreceptor Guanylyl Cyclase 1 (RetGC-1)
PMID: 15504042
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.
Insights into the pathogenesis of dominant retinitis pigmentosa associated with a D477G mutation in RPE65
PMID: 29659842
Gene: RPE65
HGNC: 10294
Disease: Retinitis pigmentosa 87 with choroidal involvement
MONDO: 0032873
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 8,000 and 1 in 27,000). The prevalence of Retinitis pigmentosa 87 with choroidal involvement is considered to be much lower.
Penetrance: Incomplete penetrance, estimated at 80%
In family 2, eye and lung diseases were also associated in two generations, both occurred later and lung disease was moderate (bronchiectasis).
FamilyLabel: Meunier_2016_Family_2
Family#PresentingHPOs: HP:0000662 (Nyctalopia), HP:0030506 (Yellow/white lesions of the retina), HP:0011510 (Drusen), HP:0007663 (Reduced visual acuity), HP:0000529 (Progressive visual loss), HP:0011506 (Choroidal neovascularization), HP:0007401 (Macular atrophy), HP:0007703 (Abnormality of retinal pigmentation), Bronchial wall thickening HP:0033542
FamilyHPOFreeText: Both eye and lung disease presented at later ages within members of this family. Eye disease onset occurred in the fifth decade of life with nyctalopia as the first presenting phenotype, and drusen / yellow lesions detectable at the posterior pole and in the peripheral retina. Choroidal neovascularization occurred during the 5th and 6th decades of life and led to progressive loss of vision in both eyes. Macular atrophy and retinal pigment abnormalities were also late presenting phenotypes. In addition to bronchial wall thickening, mild cylindrical bronchiectasis and asthma were each observed in one affected family member. Pulmonary symptoms were late in onset and only detected by CT imaging.
FamilyNotHPOs: HP:0025223 (Triggered by smoking), HP:0002097 (Emphysema),
FamilyNotHPOFreeText: No history of smoking
CountryOrigin: Family origin was not reported.
Family#PreviousTesting: Clinical exams to detail features of affected family members.
Family#GenotypingMethod: Sanger sequencing of PCR products from TIMP3 exons 1 through 5.
Affected: 4
Unaffected: 3
Segregations: 3
**PublishedLOD: N/A
eLOD: N/A
AddSegregationInfo: Insufficient number of segregations to estimate LOD score.
ProbandLabel: Meunier_2016_Family_2_patient_III-2
Variant: NM_000362.5(TIMP3):c.113C>G (p.Ser38Cys) is a missense variant predicted to introduce a new cysteine-encoding codon into exon 1. Interestingly, it differs from most other published missense variants in that it affects a codon within exon 1 rather than exon 5.
ClinVar: 843268
gnomAD: Variant is absent from gnomAD.
FamilyAddInfo: N/A
FamilyPMIDs: Family has not been previously described but the same variant has been published in PMID:23023527, PMID:26493035, and PMID:30668888 (without reporting pulmonary symptoms in either study).
retinitis pigmentosa, impaired hearing, and sinorespiratory infections
Case#: Zito_2003_Family_4462_Patient_IV.3, male, age 25 years. ethnicity not specified
CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000662 (Nyctalopia), HP:0001133 (Constriction of peripheral visual field), HP:0000618 (Blindness), HP:0007737 (Bone spicule pigmentation of the retina), HP:0000545 (Myopia), HP:0007663 (Reduced visual acuity), HP:0410018 (Recurrent ear infections), HP:0000365 (Hearing impairment), HP:0011108 (Recurrent sinusitis), HP:0002783 (Recurrent lower respiratory tract infections), HP:0002837 (Recurrent bronchitis), HP:0100582 (Nasal polyposis), HP:0000083 (Renal insufficiency)
CaseHPOFreeText: The proband has been diagnosed with retinitis pigmentosa, with the family exhibiting an X-linked pattern of inheritance.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: The proband and family members were subjected to haplotype analysis using microsatellite markers on the X chromosome.
CaseMethod1: Haplotype analysis
CaseMethod2: Sanger sequencing of PCR products from the RP2, RPGR, and TCTE1L loci
CaseGenotypingMethod: The proband and family members were subjected to haplotype analysis using microsatellite markers on the X chromosome, followed by Sanger sequencing of PCR products from the RP2, RPGR, and TCTE1L loci.
Variant: The proband harbors the NM_001034853.2(RPGR):c.789_790del (p.Thr265fs) variant in the hemizygous state.
ClinVar: 9915
gnomAD: The variant was not found in gnomAD v.2.1.1.
VariantEvidence: NM_001034853.2(RPGR):c.789_790del (p.Thr265fs) is a frameshift variant in exon 8 of exon 15 that is predicted to trigger nonsense-mediated decay or at least to disrupt ~68% of the C-terminus of the protein product.
CaseAddInfo: The proband is a member of Family 4462 (shown in Figure 1), which includes two other affected genotype-positive males and two confirmed carrier females described as having myopia and sparse peripheral intra-retinal pigmentation.
CasePMIDs: N/A
We report here the identification of an unexpected abnormality in melanosome distribution both in retinal pigment epithelium (RPE) and skin melanocytes of Oa1-knock-out (KO) mice, consisting in a displacement of the organelles from the central cytoplasm towards the cell periphery. Despite their depletion from the microtubule (MT)-enriched perinuclear region, Oa1-KO melanosomes were able to aggregate at the centrosome upon disruption of the actin cytoskeleton or expression of a dominant-negative construct of myosin Va. Consistently, quantification of organelle transport in living cells revealed that Oa1-KO melanosomes displayed a severe reduction in MT-based motility; however, this defect was rescued to normal following inhibition of actin-dependent capture at the cell periphery. Together, these data point to a defective regulation of organelle transport in the absence of OA1 and imply that the cytoskeleton might represent a downstream effector of this receptor. Furthermore, our results enlighten a novel function for OA1 in pigment cells and suggest that ocular albinism type 1 might result from a different pathogenetic mechanism than previously thought, based on an organelle-autonomous signalling pathway implicated in the regulation of both membrane traffic and transport.
ExperimentName: Continued studies of mouse model with hemizygous disruption of the GPR143 ortholog Oa1
NonHumanModel: Mus musculus
GeneAlteration: A hemizygous mouse model of Oa1 knockout was previously generated by replacement of exon 1 (including the start codon) with a cassette to facilitate selection (PMID: 11092754).
ModelPhenotype: HP:0003593 (Infantile onset), HP:0005592 (Giant melanosomes in melanocytes), severely reduced microtubule-based motility in melanosomes
HumanPhenotype: HP:0000639 (Nystagmus), HP:0003593 (Infantile onset), HP:0007663 (Reduced visual acuity), HP:0001361 (Nystagmus-induced head nodding), HP:0000646 (Amblyopia), HP:0000483 (Astigmatism), HP:0000613 (Photophobia), normally pigmented skin and hair, HP:0005592 (Giant melanosomes in melanocytes), HP:0007750 (Hypoplasia of the fovea), HP:0007894 (Hypopigmentation of the fundus), HP:0025551 (Optic nerve misrouting)
ModelEvidence: The mice match the human patients in that they exhibit congenital onset of cytological abnormalities (PMID: 16303920), These were previously shown in the RPE and are here shown in the melanocytes as well (Figure 3). Most importantly, this study shows a defect in microtubule-based melanosome motility (Figure 7), indicating an underlying mechanism for the disease.
ModelVariant: This model features disruption of Oa1 by knockout, but does not harbor a mutation equivalent to a variant from a human patient.
In the zebrafish model, lrp5 downregulation using morpholinos led to significant abnormalities in zebrafish inner ear and lateral line neuromasts and contributed, to some extent, to disabilities in hearing and balance. Rescue experiments showed that LRP5 mutation is associated with hearing loss. Knocking down lrp5 in zebrafish results in reduced expression of several genes linked to Wnt signaling pathway and decreased cell proliferation when compared with those in wild-type zebrafish.
Does model have relevance to bone density or retinal function?
Codons 837 and 838 in the retinal guanylate cyclase gene on chromosome 17p: hot spots for mutations in autosomal dominant cone-rod dystrophy?
PMID: 10676808
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.
Genotype-Dependent Variability in Residual Cone Structure in Achromatopsia: Toward Developing Metrics for Assessing Cone Health
PMID: 25277229
GeneName: GNAT2
HGNC: 4394
Disease: achromatopsia 4
MonDO ID: MONDO_0013465
Inheritance: autosomal recessive
a novel CABP4 variation was identified in one family.
Case#: Hove_2016_Proband_59, sex not reported, onset in early childhood, family ancestry reported as Danish
CasePresentingHPOs: HP:0007750 (foveal hypoplasia)
CaseHPOFreeText: The proband has a diagnosis of Aland Island eye disease and showed foveal hypoplasia in both eyes (supplement 2).
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous genotyping may have been limited to Sanger sequencing of PCR products from the CACNA1F gene, or may have performed screening of other known genes associated with this phenotype.
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 panel-based sequencing of other inherited retinal disease-associated genes.
Variant: The individual harbors the NM_145200.5(CABP4):c.773A>T (p.Asn258Ile) variant in the homozygous state.
ClinVar ID: 636004
gnomAD: The variant is found in gnomAD version 4.1.1 at a frequency of 0.000001695 in the European (non-Finnish) population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/chr11-67458492-A-T?dataset=gnomad_r4
VariantEvidence: NM_145200.5(CABP4):c.773A>T (p.Asn258Ile) is a missense variant that does not have a characterized functional impact on CABP4..
CaseAddInfo: No details are available regarding the potential for parental consanguinity.
CasePMIDs: N/A
Within the PRPF4 sequence, we identified two annotated variants, p.His78Arg and p.Pro187Ala (Table 2). The first one corresponded to dbSNP entry rs1138958 and was present in 60 European heterozygotes from the Exome Variant Server database; therefore, we considered the variant to be non-pathogenic. The second variant, found in a single individual (ID: 001–417), involved nucleotide c.559C (NM_004697.3, exon 5), which was flagged in dbSNP as entry rs187531407 and referred to a CCC>TCC (p.Pro187Ser) change, found only in two non-validated 1000 Genomes reports. We ascertained that one of these reports (a low-coverage genome in an African sample) was a false positive, following validation with direct Sanger sequencing on the original DNA sample (ID: NA18933, Coriell DNA repository). Moreover, although the nucleotide is the same, the base change in the patient in our cohort was different compared to rs187531407. More specifically, we identified a CCC>GCC change, which resulted in p.Pro187Ala. Proline 187 is not fully conserved across different species and, according to predictions with different tools, the likelihood of pathogenicity of p.Pro187Ala is uncertain (Table 3). We followed up this change by analyzing controls and available relatives. Public databases, as well as sequencing of in-house controls, did not reveal the presence of this change. We then screened an additional 202 patients with adRP from the same cohorts for this specific variant, but this change was not found in any additional individuals. The affected sibling (ID: 226–1953) of the index patient also carried the same change, but other family members were not available for further segregation analysis. Since the base change is located within exon 5, at a 5-bp distance from the donor splice site, we also checked if splicing of this exon was affected. Bioinformatic prediction was negative, and reverse-transcription (RT)–PCR of patient’s cDNA did not reveal missplicing events. In the absence of additional elements, we could neither exclude nor validate this change as a potential mutation.
Case#: Benaglio_2014_Proband_001-417, sex not reported, age not reported, national origin German
CasePresentingHPOs: N/A
CaseHPOFreeText: The proband has been diagnosed with autosomal dominant retinitis pigmentosa.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous testing in the proband consisted of screening either by Sanger sequencing of 90% of known adRP genes, by genotyping microarray of known RP variants, or sequencing-based genotyping of RHO, RDS, PRPF31, RP1, PRPF8, IMPDH1, NRL, PRPF3, NR2E3, and SNRNP200.
CaseMethod1: next-generation sequencing of PRPF4 and EFTUD2 genes
CaseMethod2: Sanger sequencing of the coding regions of NHP2L1 and AAR2
CaseGenotypingMethod: Genotyping of the proband initially consisted of either Sanger sequencing of 90% of known adRP genes, genotyping microarray of known RP variants, or sequencing-based genotyping of RHO, RDS, PRPF31, RP1, PRPF8, IMPDH1, NRL, PRPF3, NR2E3, and SNRNP200. Subsequent genotyping was performed by next-generation sequencing of PRPF4 and EFTUD2 genes and Sanger sequencing of the coding regions of NHP2L1 and AAR2.
Variant: The proband harbors the NM_001244926.2(PRPF4):c.556C>G (p.Pro186Ala) variant in the heterozygous state.
ClinVar ID: 865751
gnomAD: The NM_001244926.2(PRPF4):c.556C>G (p.Pro186Ala) variant is found in gnomAD v4.1.0 at a frequency of 0.00006609 (90 alleles / 1180038 total alleles, with 0 homozygotes) in the European (non-Finnish) population https://gnomad.broadinstitute.org/variant/9-113283207-C-G?dataset=gnomad_r4
VariantEvidence: NM_001244926.2(PRPF4):c.556C>G (p.Pro186Ala) is a missense variant located 5 bp from the 3' end of exon 5 with no direct evidence of an abnormal impact on the PRPF4 protein.
CaseAddInfo: The proband has an affected sibling who also harbors the variant.
CasePMIDs: N/A
prpf4 is essential for cell survival and posterior lateral line primordium migration in zebrafish
PMID: 30174136
GUCY2D Cone–Rod Dystrophy-6 Is a “Phototransduction Disease” Triggered by Abnormal Calcium Feedback on Retinal Membrane Guanylyl Cyclase 1
PMID: 29440533
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.
Whole exome sequencing identifies a novel splice-site mutation in IMPG2 gene causing Stargardt-like juvenile macular dystrophy in a north Indian family
PMID: 34990796
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.
All four proteins, NR2E3, NR1D1, NRL and CRX, could be co-immunoprecipitated from the bovine retinal nuclear extract, suggesting their existence in a multi-protein transcriptional regulatory complex in vivo. Our results demonstrate that NR2E3 is involved in regulating the expression of rod photoreceptor-specific genes and support its proposed role in transcriptional regulatory network(s) during rod differentiation.
ExperimentName: NR2E3 physical interaction with NRL and CRX
InteractingGene: HGNC:8002 (NRL), HGNC:2383 (CRX)
InteractionType: Physical interaction
InteractionMethod: Co-immunoprecipitation
InteractionEvidence: Immunoprecipitation of NR2E3, NRL or CRX from bovine retinal nuclear extract successfully led to co-immunoprecipitation of the others, indicating their presence in a transcriptional regulatory complex (Figure 6).
Splice-site mutations identified in PDE6A responsible for retinitis pigmentosa in consanguineous Pakistani families
PMID: 26321862
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.
A mutant TIMP-3 in which serine 181 was changed to a cysteine, found in Sorsby's fundus dystrophy, a hereditary macular degenerative disease, was also expressed in COS-7 cells. This gave rise to an additional 48-kDa species (possibly a TIMP-3 dimer) that retained its ability to inhibit MMPs and localize to the ECM.
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: A TIMP3 expression construct encoding the "Ser181Cys" variant (more accurately referred to as a Ser204Cys variant) was generated by PCR using a 3' primer that contained the desired substitution.
FunctionalEvidence: The TIMP3 variant was exogenously expressed in COS-7 cells alongside a mock transfected control (not a wild-type control). Reverse zymography of extracellular matrix from these cells revealed the presence of both a monomeric and a dimeric species with metalloproteinase inhibitory activity (Figure 4). This was confirmed by immunoblotting to be TIMP3, and the dimeric species appeared under non-reducing conditions but disappeared under reducing conditions (Figure 5). This indicated that the free cysteine present in the variant may not have compromised metalloproteinase inhibitory activity, but likely facilitated an intramolecular disfulfide bonding interaction with another TIMP3 molecule. This gain-of-function interpretation of the variant effect would be consistent with the autosomal dominant mechanism of its inheritance. The wild-type control was absent from this figure. It is not clear whether a separate but similar figure showing the wild-type control was performed under reducing or non-reducing conditions.
FAVariants: Variant used was equivalent to NM_000362.5(TIMP3):c.610A>T (p.Ser204Cys) (ClinVarID:12676). The variant is referred to in this publication 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.
frameshift
Case#: Gong_2001_Proband_3, 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.1468del (p.Asp490fs) variant in the homozygous state.
ClinVar: 6270
gnomAD: The NM_002335.4(LRP5):c.1468del (p.Asp490fs) variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_002335.4(LRP5):c.1468del (p.Asp490fs) is a frameshift variant in exon 7 out of 23 that is predicted to trigger nonsense-mediated decay or at least to truncate the C-terminal ~70% of the protein product.
CaseAddInfo: The family is reportedly consanguineous.
CasePMIDs: PMID: 8659519
A dominant mutation in RPE65 identified by whole-exome sequencing causes retinitis pigmentosa with choroidal involvement
PMID: 21654732
Gene: RPE65
HGNC: 10294
Disease: Retinitis pigmentosa 87 with choroidal involvement
MONDO: 0032873
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 8,000 and 1 in 27,000). The prevalence of Retinitis pigmentosa 87 with choroidal involvement is considered to be much lower.
Penetrance: Incomplete penetrance, estimated at 80%
cGMP phosphodiesterase-alpha mutation causes progressive retinal atrophy in the Cardigan Welsh corgi dog
PMID: 10393029
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.
One construct was designed to replace the endogenous mouse Opn1mw gene with a human cDNA encoding a normal L cone opsin with the following amino acids at the polymorphic positions encoded by exon 2, 3 and 4: T65, I111, S116, L153, I171, A174, I178, S180, I230, A233, and M236. The modified locus in mice in this study was Opn1lwLIAIS/LIAIS for females or Opn1lwLIAIS/Y for males, but for simplicity, here the locus is referred to as Opn1lwLIAIS. The second construct was designed to create a large deletion within the mouse Opn1sw gene, thereby creating an S-opsin knockout mouse, designated Opn1sw−/−.
ExperimentName: OPN1LW rescue of mice with Opn1mw and Opn1sw defects
RescueModel: Mus musculus
GeneAlteration: Rescue was performed by replacing the endogenous Opn1mw gene with a known benign OPN1LW LIAIS compound variant from unaffected humans, which serves as a wild-type OPN1LW control.
RescueVariant: Rescue was performed by replacing the endogenous Opn1mw gene with a known benign OPN1LW LIAIS compound variant from unaffected humans, which serves as a wild-type OPN1LW control.
RescuePhenotype: The rescued phenotypes are cone outer segment length and number.
RescueMethod: This rescue model has replacement of the mouse Opn1mw gene with a normal variant of human OPN1LW.
RescueEvidence: Replacement of the mouse Opn1mw gene with a normal variant of human OPN1LW results in a shift in sensitivity to detect red wavelengths (Figure 5) and rescues a defect in outer segment length caused by knockout of both Opn1mw and Opn1sw (Figure 13).
ModelVariant: The model harbors homozygous deletion of Opn1sw and either intact Opn1mw or replacement of Opn1mw with human OPN1LW.
The genetic landscape of inherited eye disorders in 74 consecutive families from the United Arab Emirates
PMID: 32783370
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.
A BBS1 SVA F retrotransposon insertion is a frequent cause of Bardet-Biedl syndrome
PMID: 33169370
Gene: BBS1
HGNC: 966
Disease: Bardet-Biedl syndrome 1
MONDO: 0008854
InheritancePattern: autosomal recessive
Prevalence: The prevalence of BBS1 variants among Bardet-Biedl syndrome cohorts has been reported as at least 20% (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.