S30
Case#: S30, Iranian
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 30%
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.2090T>C
LegacyVariant:
ClinVar: No
CAID: CA414909005
gnomAD:
S17
Case#: S17, 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.1063C>T
LegacyVariant:
ClinVar: No
CAID: CA255031
gnomAD:
S1
Case#: S1, Iranian
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
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: NM_000132.3:c.209_212del
LegacyVariant:
ClinVar: No
CAID: CA255050
gnomAD:
S22
Case#: S22, 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:
S9
Case#: S9, Iranian
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
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: NM_000132.3:c.2945dupA
LegacyVariant:
ClinVar: No
CAID: CA255142
gnomAD:
S2
Case#: S2, 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:
S21
Case#: S21, 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.6213A>T
LegacyVariant:
ClinVar: No
CAID: CA414903164
gnomAD:
S24
Case#: S24, Iranian
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Mucosal bleeding, 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.5509A>T
LegacyVariant:
ClinVar: No
CAID: CA414908661
gnomAD:
B76
Case#: B76
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C Chr = 7, FVIII:AG = 10, inverse 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.5398C>G
LegacyVariant:
ClinVar: No
CAID: CA255164
gnomAD:
B45 – B72
Case#: B45 - B72
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C Chr = 9, FVIII:AG = 16, inverse 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.5096A>T
LegacyVariant:
ClinVar: No
CAID: CA255022
gnomAD:
Table 2
Case#: Cz2, 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#: Cz34, Italy (Calabria)
DiseaseAssertion: Hemophilia A
FamilyInfo: Inherited
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVII:C 4%
CasePreviousTesting: Polymerase chain reaction (PCR) analysis, Long PCR for detecting the intron 22 inversion was performed, Direct cycle sequence analysis using the Taq dye-deoxy terminator method
Gene: F8
Variant: NM_000132.3:c.1538-18G>A
ClinVar: 811357 https://www.ncbi.nlm.nih.gov/clinvar/variation/811357/
CAID: CA873354114
gnomAD: Not reported
Table 1
Case#: Cz21, 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: F8, IVS22 INV
ClinVar: 10150 https://www.ncbi.nlm.nih.gov/clinvar/variation/10150/
CAID: NA
gnomAD: Not reported
Table 1
Case#: Cz14, 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(F8):c.5953C>T (p.Arg1985Ter)
ClinVar: 10300 https://www.ncbi.nlm.nih.gov/clinvar/variation/10300/
CAID: CA255191
gnomAD: Not reported
C.6317A>C
Case#: 27
DiseaseAssertion: Hemophilia A
FamilyInfo: Positive
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.6317A>C (p.Gln2087Pro)
ClinVar: NA
CAID: CA414900070
gnomAD: Not reported
c.1706C>G
Case#: 22
DiseaseAssertion: Hemophilia A
FamilyInfo: Sporadic
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.1706C>G (p.Pro550Arg)
ClinVar: NA
CAID: CA414911701
gnomAD: Not reported
c.6135G>T
Case#: 9
DiseaseAssertion: Hemophilia A
FamilyInfo: Sporadic
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NA
ClinVar: NA
CAID: NA
gnomAD: NA
c.3093delAAGA
Case#: 4
DiseaseAssertion: Hemophilia A
FamilyInfo: Positive
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe, Inhibitors present
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3(F8):c.3091_3094del (p.Lys1031fs)
ClinVar: 369689 https://www.ncbi.nlm.nih.gov/clinvar/variation/369689/
CAID: CA645509240
gnomAD: Not reported
C.6301C>G
Case#: 26
DiseaseAssertion: Hemophilia A
FamilyInfo: Positive
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Mild
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3(F8):c.6301C>G (p.His2101Asp)
ClinVar: 804137 https://www.ncbi.nlm.nih.gov/clinvar/variation/804137/
CAID: CA414900220
gnomAD: Not reported
c.584T>C
Case#: 14, Spanish
DiseaseAssertion: Hemophilia A
FamilyInfo: Sporadic
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.584T>C (p.Leu195Pro)
ClinVar: NA
CAID: CA414919399
gnomAD: Not reported
c.5286T>A
Case#: 25
DiseaseAssertion: Hemophilia A
FamilyInfo: Sporadic
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Moderate
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.5286T>A (p.Phe1743Leu)
ClinVar: NA
CAID: CA414910973
gnomAD: Not reported
c.2766delC
Case#: 3
DiseaseAssertion: Hemophilia A
FamilyInfo: Positive
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Moderate
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.2766del (p.Leu923Ter)
ClinVar: NA
CAID: CA923726358
gnomAD: Not reported
33.
Case#: 33
DiseaseAssertion: Hemophilia B, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0011858
CaseHPOFreeText: FIX:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing
Gene: F9
Variant: NM_000133.3:c.103G>T
LegacyVariant:
ClinVar: No
CAID: CA414435383
gnomAD:
25.
Case#: 25
DiseaseAssertion: Hemophilia B, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0011858
CaseHPOFreeText: FIX:C = 2%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing
Gene: F9
Variant: NM_000133.3:c.1204G>A
LegacyVariant:
ClinVar: No
CAID: CA414446446
gnomAD:
12.
Case#: 12
DiseaseAssertion: Hemophilia B, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0011858
CaseHPOFreeText: FIX:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing
Gene: F9
Variant: NM_000133.3:c.761G>A
LegacyVariant:
ClinVar: No
CAID: CA414443235
gnomAD:
5
Case#: 5
DiseaseAssertion: Hemophilia B, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0011858
CaseHPOFreeText: FIX:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing
Gene: F9
Variant: NM_000133.3:c.305G>T
LegacyVariant:
ClinVar: No
CAID: CA414437422
gnomAD:
41.
Case#: 41
DiseaseAssertion: Hemophilia B, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0011858
CaseHPOFreeText: FIX:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing
Gene: F9
Variant: NM_000133.3:c.1135C>T
LegacyVariant:
ClinVar: No
CAID: CA255391
gnomAD:
17.
Case#: 17
DiseaseAssertion: Hemophilia B, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0011858
CaseHPOFreeText: FIX:C = 3%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: All relevant sequences of F9 were PCR amplified and analyzed by DNA sequencing
Gene: F9
Variant: NM_000133.3:c.1025C>T
LegacyVariant:
ClinVar: No
CAID: CA255381
gnomAD:
Thr37 mutation
Case#: Pezeshkpoor_Patient_M (male, 58 y/o, from Switzerland)
DiseaseAssertion: Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: spontaneous bleeding symptoms from the blood, the mouth, the tongue, and epiglottis, low FIX:C levels
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.109G>A (p.Ala37Thr)
ClinVar: 804089
CAID: CA10529736
gnomAD: Allele Frequency in population where variant was found in the highest (South Asian population): 0.0001128
071–2036
Case#: 071-2036
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:
038–1010
Case#: 038-1010
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: No
gnomAD:
071–2001
Case#: 071-2001
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.901C>T
LegacyVariant:
ClinVar: No
CAID: CA414917990
gnomAD:
035–2013
Case#: 035-2013
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.5275G>A
LegacyVariant:
ClinVar: No
CAID: CA414911087
gnomAD:
091–2010
Case#: 091-2010
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1475A>G
LegacyVariant:
ClinVar: No
CAID: CA337334224
gnomAD:
071–2023
Case#: 071-2023
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.2167G>A
LegacyVariant:
ClinVar: No
CAID: CA255138
gnomAD:
047–2001
Case#: 047-2001
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.3637delA
LegacyVariant:
ClinVar: No
CAID: CA255146
gnomAD:
084–2001
Case#: 084-2001
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.100delG
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
091–2005
Case#: 091-2005
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.5393C>A
LegacyVariant:
ClinVar: No
CAID: CA414909064
gnomAD:
020–2054
Case#: 020-2054
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.1899G>T
LegacyVariant:
ClinVar: No
CAID: CA414910251
gnomAD:
001–2050
Case#: 001-2050
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.4011insA
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
060–2004
Case#: 060-2004
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.272T>C
LegacyVariant:
ClinVar: No
CAID: CA414920117
gnomAD:
004–2012
Case#: 004-2012
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.3637delA
LegacyVariant:
ClinVar: No
CAID: CA255146
gnomAD:
020–2063
Case#: 020-2063
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.558C>G
LegacyVariant:
ClinVar: No
CAID: CA414919454
gnomAD:
002–1002
Case#: 002-1002
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant:
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
072–2007
Case#: 072-2007
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.5686_5687insA
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
071–2035
Case#: 071-2035
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:
020–2020
Case#: 020-2020
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.3637delA
LegacyVariant:
ClinVar: No
CAID: CA255146
gnomAD:
001–2025
Case#: 001-2025
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.986G>A
LegacyVariant:
ClinVar: No
CAID: CA255089
gnomAD:
010–1002
Case#: 010-1002
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant:
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
020–2038
Case#: 020-2038
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1834C>T
LegacyVariant:
ClinVar: No
CAID: CA255129
gnomAD:
015–2011
Case#: 015-2011
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.1241A>G
LegacyVariant:
ClinVar: No
CAID: CA414915839
gnomAD:
086–2006
Case#: 086-2006
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.1537G>C
LegacyVariant:
ClinVar: No
CAID: CA414912560
gnomAD:
020–2013
Case#: 020-2013
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.5368_5370delATC
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
001–2041
Case#: 001-2041
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.2167G>A
LegacyVariant:
ClinVar: No
CAID: CA255138
gnomAD:
17
Case#: 17, male, 10 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.2404C>T
LegacyVariant:
ClinVar: No
CAID: CA414901774
gnomAD:
140
Case#: 140, 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.dup exons1_22
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
153
Case#: 153, male, 52 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.3409_3410delCT
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
176
Case#: 176, male, 18 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.del exon6
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
89
Case#: 89, male, 36 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6406G>A
LegacyVariant:
ClinVar: No
CAID: CA414899430
gnomAD:
136
Case#: 136, male, 20 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
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 exon14
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
162
Case#: 162, male, 27 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.3637delA
LegacyVariant:
ClinVar: No
CAID: CA255146
gnomAD:
30
Case#: 30, male, 27 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 4.1%
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.361G>A
LegacyVariant:
ClinVar: No
CAID: CA414919926
gnomAD:
81
Case#: 81, male, 19 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 7.1%
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.5707G>A
LegacyVariant:
ClinVar: No
CAID: CA414907751
gnomAD:
128
Case#: 128, male, 10 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.3637dupA
LegacyVariant:
ClinVar: No
CAID: CA10568191
gnomAD:
62
Case#: 62, male, 50 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 38.5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.2111C>T
LegacyVariant:
ClinVar: No
CAID: CA414908864
gnomAD:
147
Case#: 147, male, 22 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.1126delG
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
158
Case#: 158, male, 7 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 14.3%
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.3637delA
LegacyVariant:
ClinVar: No
CAID: CA255146
gnomAD:
180
Case#: 180, male, 13 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 exon14
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
46
Case#: 46, male, 21 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
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.1172G>A
LegacyVariant:
ClinVar: 10111
CAID: CA120918
gnomAD:
167
Case#: 167, male, 18 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
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.5046delC
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
53
Case#: 53, male, 21 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 15.9%
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.1834C>T
LegacyVariant:
ClinVar: 10236
CAID: CA255129
gnomAD:
70
Case#: 70, male, 16 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
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.5398C>T
LegacyVariant:
ClinVar: 10275
CAID: CA255163
gnomAD:
31
Case#: 31, male, 41 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.361G>A
LegacyVariant:
ClinVar: No
CAID: CA414919926
gnomAD:
133
Case#: 133, male, 59 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.4599_4600dup
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
171
Case#: 171, male, 7 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 exons1_14
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
21
Case#: 21, male, 16 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.6403C>T
LegacyVariant:
ClinVar: 10088
CAID: CA255011
gnomAD:
94
Case#: 94, male, 8 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 8.5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6448G>A
LegacyVariant:
ClinVar: No
CAID: CA414907951
gnomAD:
3
Case#: 3, male, 39 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.616G>T
LegacyVariant:
ClinVar: No
CAID: CA414919319
gnomAD:
27
Case#: 27, male, 30 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.266G>C
LegacyVariant:
ClinVar: No
CAID: CA414920127
gnomAD:
mutations in the factor IX gene resulting in hemophilia B
Case#: Gostout_Proband_189 (assumed male, Asian (from India))
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: None
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (FIX:C: 3%)
CaseNotHPOs: None
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.127C>T (p.Arg43Trp)
LegacyVariant: c.6364C>T (p.Arg-4Trp)
ClinVar: 811505
CAID: CA414435537
gnomAD: Absent/Not Reported
mutations in the factor IX gene resulting in hemophilia B.
Case#: Gostout_Proband_280 (assumed male, Asian (from Japan))
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: None
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (FIX:C: 1.8%)
CaseNotHPOs: None
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
Molecular defects in haemophilia B: detection by direct restriction enzyme analysis
PMID: 1680373
Gene: F9
HGNC: 3551
UQU-HB4
Case#: UQU-HB4, Male, 6-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe, PTT 60.1
CasePreviousTesting: Screened for all factor IX exons by capillary 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
UQU-HB2
Case#: UQU-HB2, Male, 2-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe, PTT 74.5, Disabled right knee
CasePreviousTesting: Screened for all factor IX exons by capillary sequencing
Gene: F9
Variant: NM_001313913.1:c.580G>A (p.Asp194Asn)
ClinVar: NA
CAID: CA414441211
gnomAD: Not reported
UQU-HA38
Case#: UQU-HA36, Male, 1-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0001892 (Abnormal bleeding)
CaseHPOFreeText: Mild, FVIII: 1 to <5% (moderate HA) based on text
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.99G>T (p.Trp33Cys)
ClinVar: NA
CAID: CA414920529
gnomAD: Not reported
Compensated pathogenic variants in coagulation factors VIII and IX present complex mapping between molecular impact and hemophilia severity
PMID: 31267011
Gene: F9
HGNC: 3551
The final list of mutations is provided in Supplementary Table S1.
Case#: N/A
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: N/A
CaseHPOsFreeText: N/A
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.71T>C (p.Leu24Pro)
ClinVar: Absent
CAID: CA414434410
gnomAD: Absent/NotReported
The final list of mutations is provided in Supplementary Table S1.
Case#: N/A
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: N/A
CaseHPOsFreeText: N/A
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.59T>C (p.Leu20Ser)
ClinVar: Absent
CAID: CA414434363
gnomAD: Absent/NotReported
8
Case#: 8
DiseaseAssertion: Hemophilia B, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C = 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: All exons, UTRs, exon-intron junction regions, and the promotor of F9 were amplified by PCR and analyzed by direct DNA sequencing
Gene: F9
Variant: NM_000133.3:c.349T>C
LegacyVariant:
ClinVar: No
CAID: CA414437669
gnomAD:
16
Case#: 16
DiseaseAssertion: Hemophilia B, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C = 1.5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: All exons, UTRs, exon-intron junction regions, and the promotor of F9 were amplified by PCR and analyzed by direct DNA sequencing
Gene: F9
Variant: NM_000133.3:c.427C>G
LegacyVariant:
ClinVar: No
CAID: CA414438921
gnomAD:
11
Case#: 11
DiseaseAssertion: Hemophilia B, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: All exons, UTRs, exon-intron junction regions, and the promotor of F9 were amplified by PCR and analyzed by direct DNA sequencing
Gene: F9
Variant: NM_000133.3:c.676C>T
LegacyVariant:
ClinVar: No
CAID: CA255350
gnomAD:
c.127C>T
Case#: Meireles_Proband_4 (assumed male)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: None
ParentalTesting: None
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity
CaseNotHPOs: N/A
CasePreviousTesting: None
Gene: F9
Variant: NM_000133.4:c.127C>T (p.Arg43Trp)
ClinVar: 811505
CAID: CA414435537
gnomAD: Absent/Not Reported
F9 missense mutations impairing factor IX activation areassociated with pleiotropic plasma phenotypes
PMID: 34626083
Gene: F9
HGNC: 3551
Hb15
Case#: HB15 (assumed male, Tunisian)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: None
ParentalTesting: None
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (FIX: <1)
CaseNotHPOs: None
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
6365
Case#: Patient B (assumed male)
DiseaseAssertion: Moderate, Sporadic Hemophilia B
FamilyInfo: Patient B is deceased and only a DNA sample was available; his two sisters and mother are carriers
ParentalTesting: Mother was heterozygous for the variant
CasePresentingHPOs: None
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
LegacyVariant: c.6365 G>A (p.Arg-4Gln)
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
Table I
No evidence of NM_000133.4:c.84T>G (p.Cys28Trp) in this paper.
c.83G>A
Case#: Salviato_Proband_2164 (male, Chinese)
DiseaseAssertion: Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.83G>A (p.Cys28Tyr)
ClinVar: Absent
CAID: CA414434483
gnomAD: Absent/Not Reported
High resolution melting for F9 gene mutation analysis in patients with haemophilia B
PMID: 29517974
Gene: F9
HGNC: 3551
A homozygous female hemophilia A
PMID:22754241
Gene:F8
HGNC ID:3546
c.689G>A
Case#: 45
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C 5% (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:c.689G>A (p.Gly230Glu)
ClinVar: NA
CAID: CA414441179
gnomAD: Not reported
c.5123G>A
Case#: 20
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 18%, 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.5123G>A (p.Arg1708His)
ClinVar: 10266 https://www.ncbi.nlm.nih.gov/clinvar/variation/10266/
CAID: CA255154
gnomAD: MAF for Arg1708His in the South Asian population 0.00005507<br> https://gnomad.broadinstitute.org/variant/X-154156942-C-T?dataset=gnomad_r2_1
c.6845C>G
Case#: 36
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 33/30%, 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.6845C>G (p.Ser2282Cys)
ClinVar: NA
CAID: CA414903435
gnomAD: Not reported
c.396A>C
Case#: 3
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 18% (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.396A>C (p.Glu132Asp)
ClinVar: 10171 https://www.ncbi.nlm.nih.gov/clinvar/variation/10171/
CAID: CA255060
gnomAD: MAF for Glu132Asp in Other population 0.0003762<br> https://gnomad.broadinstitute.org/variant/X-154221416-T-G?dataset=gnomad_r2_1
c.1291T>G
Case#: 41
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C 2/2% (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:c.1291T>G (p.Trp431Gly)
ClinVar: NA
CAID: CA414447127
gnomAD: Not reported
c.580G>A
Case#: 44
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C 23% (Mild 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_001313913.1:c.580G>A (p.Asp194Asn)
ClinVar: NA
CAID: CA414441211
gnomAD: Not reported
c.2043G>A
Case#: 16
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 31% (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.2043G>A (p.Met681Ile)
ClinVar: NA
CAID: CA414909257
gnomAD: Not reported
6364 C→T
Case#: Ivaskevicius_Proband_LT65 (assumed male, Lithuanian)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (FIX:C: 0)
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.127C>T (p.Arg43Trp)
LegacyVariant: c.6364C>T (p.Arg-4Trp)
ClinVar: 811505
CAID: CA414435537
gnomAD: Absent/Not Reported
Table S1
Case#: Li_Proband_1 (male)
DiseaseAssertion: Moderate Hemophilia B
FamilyInfo: Not provided
ParentalTesting: Not provided
CasePresentingHPOs: N/A
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.82T>C (p.Cys28Arg)
ClinVar: 10657
CAID: CA255450
gnomAD: Absent/Not Reported
Case#: Patient A (assumed male)
DiseaseAssertion: Severe (sporadic) Hemophilia B
FamilyInfo: Variant also localized in affected brother, mother (Native American descent) is deceased but maternal grandmother and two maternal aunts screened negative, researchers believe this de novo mutation originated during either grandparent’s gametogenesis.
ParentalTesting: Mother deceased, no mention of father
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: FIX Clotting Activity (U/dl): < 1, Antigen Level (U/dl): < 1
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.50T>A (p.Ile17Asn)
LegacyVariant: c.79T>A (p.Ile-30Asn)
ClinVar: Absent
CAID: CA414434315
gnomAD: Absent/Not Reported
Regulation of a strong F9 cryptic 5′ss by intrinsic elements and by combination of tailored U1snRNAs with antisense oligonucleotides
PMID: 26063760
Gene: F9
HGNC: 3551
21-year-old male patient
Case1: 21 year old, male patient, bearing a F8 frameshift mutation with severe Hemophilia A.
DiseaseAssertion: Severe Hemophilia A
Variant: NM_000132.3:c.3167del
ClinVar: Not noted in ClinVar
CAID: CA915940211 (Previously not registered)
DiseaseEntity: Factor VIII deficiency
Inheritance Pattern: No inheritance assertion
Case#: Liu_Proband_56/439/440/486/830 (assumed male; Chinese)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
ClinVar: Absent
CAID: CA414435539
gnomAD: Absent/Not Reported
Case#: Liu_Proband_438 (assumed male; Chinese)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.127C>T (p.Arg43Trp)
ClinVar: Absent
CAID: CA414435537
gnomAD: Absent/Not Reported
Molecular pathology of haemophilia B: identification of five novel mutations including a LINE 1 insertion in Indian patients
PMID: 15086324
Gene: F9
HGNC: 3551
mutant factor IX
Case#: Salle_Proband_J-C L (male, 23 y/o, white)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: family history is negative for any haemostatic disorder
ParentalTesting: family history is negative for any haemostatic disorder
CasePresentingHPOs: HP:0011858, HP:0012233, HP:0000421
CaseHPOsFreeText: reduced factor IX activity (FIX:C: <0.01 % FIX:Ag: 0.46), muscular haematoma, haemarthrosis, nose bleeding
CaseNotHPOs: N/A
CasePreviousTesting: None
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
Twenty-four novel hemophilia B mutations revealed by rapid scanning of the whole factor IX gene in a French population sample
PMID: 8055323
Gene: F9
HGNC: 3551
c.83G>A/p.Cys28Tyr
Case#: Nummi_Proband_6 (assumed male)
DiseaseAssertion: Moderate Hemophilia B
FamilyInfo: N/A
ParentalTesting: None
CasePresentingHPOs: HP:0001929 (FIX baseline clotting activity: 1
CaseHPOsFreeText: reduced factor IX activity
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.83G>A (p.Cys28Tyr)
ClinVar: Absent
CAID: CA414434483
gnomAD: Absent/Not Reported
Case#: Oldenburg Cases A, B and C (A: 66 y/o, B: 38 y/o, C: 30 y/o (all in Germany))
DiseaseAssertion: Mild Hemophilia B
FamilyInfo: No bleeding tendency noted in any of these patients family history
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: severe bleeding at each occasion of oral anticoagulation with phenoprocoumon, bleeding was located in the muscles of the upper leg (patients A and C) and scrotum, left calf and thigh musles (patient B), reduced factor IX levels
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.109G>A (p.Ala37Thr)
LegacyVariant: p.Ala-10Thr
ClinVar: 804089
CAID: CA10529736
gnomAD: Allele Frequency in population where variant was found in the highest (South Asian population): 0.0001128
AdditionalCaseInfo: all patients were unrelated up to the third generation. However, the parents of patients A and C emigrated from the same region in North-Eastern Europe (North Poland)
Therapeutic potential of spheroids of stem cells from human exfoliated deciduous teeth for chronic liver fibrosis and hemophilia A
PMID: 31552493
Gene: F8
No Evidence: No mention of variants or probands in this article.
Identification and Genetic Analysis of a Factor IX Gene Intron 3 Mutation in a Hemophilia B Pedigree in China
PMID: 25330515
Gene: F9
HGNCID: 3551
p.Ala315dup (patient P2)
CaseInfo: P2 (female)
DiseaseAssertion: Carrier
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0003125, HP:0004846, HP:0001892
CaseHPOFreeText: Low FVIII levels (undetectable FVIII:C levels and significant decrease in FVIII:Ag levels: 1.7% ± 1.1), prolonged bleeding after surgery, mild bleeding tendency
CaseNotHPOs: N/A
CaseNotHPOsFreeText: N/A
CasePreviousTesting: Molecular Analysis included a southern blot assay, PCR, dHPLC and a multiplex ligation-dependent probe amplification analysis. Plasmid mutagenesis, plasmid transfection were also performed.
Gene: F8
Variant: NM_000132.3:c.943del
CAID: CAID:CA255085
gnomAD: Absent/Not Reported
Click here for additional data file.(2
NM_000133.4:c.128G>T (p.Arg43Leu) is mentioned in this paper, however, there is no case level data associated with the mentioned variant.
p.Cys28Trp
Case#: N/A
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: None
ParentalTesting: N/A
CasePresentingHPOs: HP:0001929
CasePresentingHPOsFreeText: reduced factor IX activity
CaseNotHPOs: None
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.84T>G (p.Cys28Trp)
ClinVar: Absent
CAID: CA414434487
gnomAD: Absent/Not Reported
Mutations
Case#: Weinmann_Family 9248
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: 16 of the families were from the Pacific Northwest, 4 from Colorado, and 6 were referred from elsewhere in the United States
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity (FIX:C: <1%, FIX:Ag: 37)
CaseNotHPOs: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.127C>T (p.Arg43Trp)
LegacyVariant: c.6364C>T
ClinVar: 811505
CAID: CA414435537
gnomAD: Absent/Not Reported
identify the causative mutation
Case#: Belvini_Proband_15 (male, Italian)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: N/A
ParentalTesting: N/A
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: reduced factor IX activity
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.128G>A (p.Arg43Gln)
ClinVar: 810864
CAID: CA414435539
gnomAD: Absent/Not Reported
Phase 1, single‐dose escalating study of marzeptacog alfa (activated), a recombinant factor VIIa variant, in patients with severe hemophilia
PMID: 30151972
Gene: F8
HGNC: 3546
NoEvidence: This article does not mention specific case reports with variants
Novel Mutations in Factor IX Gene From Western IndiaWith Reference to Their Phenotypic andHaplotypic Attributes
PMID: 19262239
Gene: F9
HGNC: 3551
PMID: 10094553
Gene: F9
HGNC: 3551
Fig. 1
Case#: 12 year old male
DiseaseAssertion: Hemophilia B, moderate
FamilyInfo: Mother was a carrier. Maternal uncle has the same hemizygous mutation
ParentalTesting: Family Pedigree reveals that the mother was a carrier of the variant identified in the proband
CasePresentingHPOs: HP:0011858, HP:0030839
CaseHPOFreeText: FIX:C = 1%, proband had a history of soft tissue hemorrhages since 7 years of age
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: Direct nucleotide sequencing was completed
Gene: F9
Variant: NM_000133.3:c.157G>C
LegacyVariant:
ClinVar: No
CAID: CA414435729
gnomAD:
37, G-IA
Case#: Riegelsberg (male)
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: Mother carries only the G-to-A transition (age at conception: 30 y/o). Origin of variant cannot be proved, since maternal grandparents were deceased at time of report.
ParentalTesting: Mother carries only the G-to-A transition, father shows to not be affected (figure 1)
CasePresentingHPOs: HP:0011858
CaseHPOsFreeText: FIX Coagulant %: < 1, FIX Antigen %: < 1
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
Gene: F9
Variant: NM_000133.4:c.8G>A (p.Arg3His)
LegacyVariant: c.37G>A
ClinVar: 695909
CAID: CA10529706
gnomAD: Filtering AF: 0.0002304 (no homozygotes)
A short term anatomical and visual outcomes of large idiopathic macular holes surgery following inverted internal limiting membrane fl ap technique
PMID: 31523064
Gene: F8
NoEvidence: This article does not mention Hemophilia A, or F8. No mention of blood disorders in general.
Molecular pathology of haemophilia B
PMID: 2743975
Gene: F9
HGNC: 3551
New technologies in gene therapy for inducing immune tolerance in hemophilia A
PMID: 30345839
Gene: F8
HGNC: 3546
NoEvidence: This article discusses new technologies in gene therapy for inducing immune tolerance in hemophilia A, there are no case reports with variants mentioned in this article
Night blindness in Sorsby's fundus dystrophy reversed by vitamin A
PMID: 7550309
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
FIV3
FamilyLabel: Perrault_2012_Family_FIV
Family#PresentingHPOs: HP:0003593 (Infantile onset), HP:0000639 (Nystagmus), HP:0007663 (Reduced visual acuity)
Family#PresentingHPOFreeText: Staining of ciliary axonemes for acetylated alpha-tubulin detected an absence of cilia in a high percentage of cultured fibroblast cells, relative to control patients. Affected family members have been diagnosed with Mainzer-Saldino syndrome.
FamilyNotHPOs: HP:0001410 (Decreased liver function), HP:0012211 (Abnormal renal physiology)
FamilyNotHPOFreeText: IFT140 protein localization along the ciliary axoneme was unaffected in patient FIV3, however, two components of the anterograde transport IFT-B complex, IFT88 and IFT46, were aberrantly localized. They were evenly distributed along the cilium instead of primarily localized at the base and the tip of the cilium, suggesting an alteration in retrograde ciliary transport.
CountryOrigin: Saudi Arabia
Ethnicity: Not described.
Race: Not described.
Family#PreviousTesting: N/A
FamilyMethod1: Ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes)
Family#Method2: Sanger sequencing of the 29 coding exons of IFT140.
Family#GenotypingMethod: The family was genotyped by ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes), confirmed by Sanger sequencing of the 29 coding exons of IFT140
Affected: 3
Unaffected: 3
Segregations: 2 segregation were reported. The pedigree can be found in Figure S1. The family was described as consanguineous.
PublishedLOD: N/A
eLOD: 1.50
AddSegregationInfo: N/A
ProbandLabel: Perrault_2012_patient_FIV3
Variant: Affected individuals harbor the NM_014714.4(IFT140):c.1990G>A (p.Glu664Lys) variant in a homozygous state.
ClinVar: 31679
gnomAD: The NM_014714.4(IFT140):c.1990G>A (p.Glu664Lys) variant is present in gnomAD at a frequency of 0.00004031 in the African / African-American population (1/24806, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1614075-C-T
FamilyAddInfo: The parents of the affected family members are reportedly consanguineous (first cousins).
FamilyPMIDs: N/A
Affected individuals of the nonconsanguineous simplex FII
Case#: Perrault_2012_Patient_FII1, male, 18 years of age at time of study, ethnicity not specified
CasePresentingHPOs: HP:0003577 (Congenital onset), HP:0000639 (Nystagmus), HP:0025573 (Mild myopia), HP:0007994 (Peripheral visual field loss), HP:0007663 (Reduced visual acuity), HP:0007814 (Retinal pigment epithelial mottling), HP:0000608 (Macular degeneration), HP:0000550 (Undetectable electroretinogram), HP:0010164 (Cone-shaped epiphyses of the toes), HP:0003774 (Stage 5 chronic kidney disease), HP:0002153 (Hyperkalemia), HP:0000113 (Polycystic kidney dysplasia), HP:0000556 (Retinal dystrophy), HP:0001396 (Cholestasis), HP:0010230 (Cone-shaped epiphyses of the phalanges of the hand)
CaseHPOFreeText: Photoattraction was listed as a phenotype. Acetylated alpha-tubulin staining in cultured fibroblasts showed an absence of primary cilia in a high number of cells from this patient.
CaseNotHPOs: HP:0004322 (Short stature), HP:0000773 (Short ribs), HP:0000900 (Thickened ribs), HP:0000929 (Abnormal skull morphology), HP:0040064 (Abnormality of limbs), HP:0001263 (Global developmental delay), HP:0004979 (Metaphyseal sclerosis)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
CaseMethod1: Ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes)
CaseMethod2: Sanger sequencing of the 29 coding exons of IFT140
CaseGenotypingMethod: The patient was genotyped by ciliome resequencing of a customized target enrichment library (consisting of 1,666 genes), confirmed by Sanger sequencing of the 29 coding exons of IFT140
Variant: The patient is a compound heterozygote harboring the NM_014714.4(IFT140):c.932A>G (p.Tyr311Cys) and NM_014714.4(IFT140):c.857_860del (p.Ile286LysfsTer6) variants in IFT140.
ClinVar: 31681
CAID: CA129888
gnomAD: Neither variant was found in gnomAD.
VariantEvidence: Exogenous expression of the FLAG-tagged p.Tyr311Cys variant in the RPE1 (retinal pigment epithelial) cell line revealed an inability to co-localize with gamma-tubulin, indicating a defect in localization to the basal body in most cells, although milder than another suspected pathogenic missense variant (Figure 3A). The p.Ile286LysfsTer6) variant is a frameshift variant in exon 8 of 31, introducing a premature stop codon predicted to trigger nonsense-mediated decay or at least disrupt the C-terminal 81% of the protein product.
CaseAddInfo: The proband's parents are reportedly non-consanguineous.
CasePMIDs: N/A
two
Case#: Meindl_1996_Family_RP07_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.154G>T (p.Gly52Ter) variant in the hemizygous state.
ClinVar: 98747
gnomAD: The variant was not found in gnomAD v.2.1.1.
VariantEvidence: NM_001034853.2(RPGR):c.154G>T (p.Gly52Ter) is a nonsense variant predicted to trigger nonsense-mediated decay or to at least disrupt the C-terminal 94% of the protein product.
CaseAddInfo: The proband is a member of Family RP07.
CasePMIDs: N/A
SFD pedigrees
FamilyLabel: Weber_1994_Family_M
Family#PresentingHPOs: HP:0011506 (Choroidal neovascularization), HP:0025094 (Disciform macular scar), HP:0007663 (Reduced visual acuity)
FamilyHPOFreeText: Choroidal neovascular invasion of the macula was bilateral. This occurred early in the presentation and led to the disciform scar and loss of central vision.
FamilyNotHPOs: N/A
CountryOrigin:
Family#PreviousTesting:
Family#GenotypingMethod: Sanger sequencing of Weber_1994_Family_M_patient_IV-2
Affected: 1
Unaffected: 1
Segregations: N/A
PublishedLOD:
eLOD: Insufficient information available
AddSegregationInfo: Absence of segregation info from the family is due to the fact that genotyping was limited to only the proband and one unaffected control.
ProbandLabel: Weber_1994_Family_M_patient_IV-2
Variant: NM_003490.4:c.711+5602T>C, p.Tyr191Cys
ClinVar: 12677
gnomAD: Variant is absent from gnomAD.
FamilyAddInfo: Variant was first referred to in PMID:7894485 as "Tyr168Cys" but encodes Tyr191Cys in the updated polypeptide sequence.
FamilyPMIDs: PMID:2000899
We report two Italian siblings presenting in their mid-50s with difficulty in walking, dysarthria and progressive cognitive decline. Visual loss, ascribed to glaucoma, manifested a few years before the other symptoms. Brain MRI showed severe cerebellar atrophy, prevalent in the vermis, with marked cortical atrophy of both hemispheres. Exome sequencing identified a novel homozygous mutation (c.935G > A;p.Ser312Asn) in the ceroid neuronal lipofuscinosis type 5 gene (CLN5).
FamilyLabel: Mancini_2015_Family_ATA-7-TO
FamilyPresentingHPOs: HP:0003596 (Middle age onset), HP:0002355 (Difficulty walking), HP:0001260 (Dysarthria), HP:0001268 (Mental deterioration), HP:0000572 (Visual loss), HP:0001272 (Cerebellar atrophy), HP:0006855 (Cerebellar vermis atrophy), HP:0008278 (Cerebellar cortical atrophy), HP:0001251 (Ataxia), HP:0002317 (Unsteady gait), HP:0000639 (Nystagmus), HP:0001310 (Dysmetria), HP:0007350 (Hyperreflexia in upper limbs), HP:0002395 (Lower limb hyperreflexia)
FamilyPresentingHPOFreeText: Presentation was in the middle of the 6th decade of life.
FamilyNotHPOs: HP:0410280 (Pediatric onset), HP:0003474 (Somatic sensory dysfunction)
FamilyNotHPOFreeText: N/A
CountryOrigin: Italy (North-West)
Ethnicity: Italian
Race: Not mentioned
Family#PreviousTesting: Previous testing was limited to molecular tests ruling out Friedreich Ataxia and Spinocerebellar Ataxia types 1 and 2.
Family#Method1: N/A
Family#Method2: N/A
Family#GenotypingMethod: Whole exome sequencing of the proband and the affected sibling. Homozygosity was assumed due to the consanguinity of the family, contributing to the decision to focus on the variant in CLN5. This variant was confirmed by Sanger sequencing of PCR products from exon 4 of the CLN5 gene in both affected family members and an additional unaffected sibling. Parents were not subjected to genotyping.
Affected: 2
Unaffected: 1
Segregations: 1 segregation was reported, with none inconsistent (see pedigree in Figure 1A). The patient's family is consanguineous, with the parents being first cousins.
PublishedLOD: N/A
eLOD: N/A
AddSegregationInfo: N/A
ProbandLabel: Mancini_2015_Patient_III-5
Variant: The proband is homozygous for the NM_006493.4(CLN5):c.788G>A (p.Ser263Asn) variant.
ClinVar: 183049 (homozygous)
gnomAD: The maximum allele frequency for the NM_006493.4(CLN5):c.788G>A (p.Ser263Asn) variant is 0.000008805 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/13-77574815-G-A
FamilyAddInfo: N/A
FamilyPMIDs: N/A
retrospective study
Case#: Olivier_2021_Family_D_Proband_II:2, male, age 58 years at the time of report, national origin reported as Spanish
CasePresentingHPOs: HP:0007737 (Bone spicule pigmentation of the retina), HP:0007843 (Attenuation of retinal blood vessels), HP:0030629 (Perifoveal ring of hyperautofluorescence)
CaseHPOFreeText: The proband and his sibling have been diagnosed with autosomal recessive retinitis pigmentosa, with clinical signs in the fundus reportedly consistent with this diagnosis.
CaseNotHPOs: HP:0040049 (Macular edema), HP:0030500 (Yellow/white lesions of the macula)
CaseNotHPOFreeText: N/A
CasePreviousTesting: It is not clear whether previous testing methods included systematic genotyping of loci associated with VMD or RP.
CaseMethod1: Screening of IMPG1 using either gene panel testing or exome sequencing
CaseMethod2: Sanger sequencing-based confirmation
CaseGenotypingMethod: Genotyping is not entirely clear but has at least included panel-based analysis of the IMPG1 locus and Sanger sequencing-based confirmation.
Variant: The proband harbors the NM_001563.4(IMPG1):c.1875A>G (p.Ile625Met) variant in the homozygous state.
CAID: CA364775681
gnomAD: This variant is not found in gnomAD v2.1.1.
VariantEvidence: NM_001563.4(IMPG1):c.1875A>G (p.Ile625Met) is a missense variant that lacks evidence of a functional impact on the protein product.
CaseAddInfo: The patient's sister is similarly affected with the same homozygous genotype, while an unaffected sister harbored the variant in the heterozygous state. Parental consanguinity is not reported but family origin is from a small village.
CasePMIDs: N/A
Isolation and characterization of cGMP phosphodiesterase from bovine rod outer segments
PMID: 227876
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.
In this study, we reinvestigated a large, highly consanguineous Finnish family previously diagnosed as having early-onset autosomal recessive SFD.
FamilyLabel: Felbor_1997_Family_1
Family#PresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0001089 (Iris atrophy), HP:0007703 (Abnormality of retinal pigmentation), HP:0000501 (Glaucoma)
FamilyHPOFreeText: Early onset of visual loss between the second and fourth decade of life, with the first sign in young family members being uneven or absent pigmentation in the extreme fundus periphery. Affected individuals experienced progressive vision loss, iris atrophy, and glaucoma in some cases.
FamilyNotHPOs: N/A
FamilyNotHPOFreeText: N/A
CountryOrigin: Finland
Family#PreviousTesting: Single-stranded conformational analysis (SSCA) of the coding and promoter regions of TIMP3, detecting a mobility shift in exon 5 that was specific to affected individuals. Sanger sequencing of PCR products from exon 5 of the TIMP3 gene, in samples from the proband and a control individual.
Family#GenotypingMethod: Enzymatic digestion of TIMP3 exon 5 PCR products with the HaeIII restriction endonuclease.
Affected: 9
Unaffected: 9
Segregations: 8
PublishedLOD: Maximum LOD score, Zmax, was reported as 3.03 (at theta = .001, for the D22S281 marker, previously linked to the TIMP3 locus in PMID:8919688)
eLOD: 2.4
AddSegregationInfo: N/A
ProbandLabel: Felbor_1997_Family_1_patient_III-4
Variant: Affected patients harbor the NM_000362.5(TIMP3):c.565G>T (p.Gly189Cys) missense variant.
ClinVar: 12679
gnomAD: Variant is absent from gnomAD.
FamilyAddInfo: This highly consanguineous family was previously proposed to show an autosomal recessive pattern of inheritance (not previously observed for Sorsby fundus dystrophy). The family has been genotyped for the first time in this study, revealing segregation of disease phenotypes with a heterozygous variant in TIMP3, with autosomal dominant inheritance.
FamilyPMIDs: PMID:7148944, PMID:2387082
A null mutation in the photoreceptor guanylate cyclase gene causes the retinal degeneration chicken phenotype
PMID: 9448321
Gene: GUCY2D
HGNC: 4689
Disease: Leber congenital amaurosis 1
MONDO: 0008764
InheritancePattern: Autosomal Recessive
Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by GUCY2D variants is between 10% and 20% (PMID: 10951519). Thus, the prevalence of Leber congenital amaurosis 1 is between 1 in 165,000 and 1 in 1,000,000.
Penetrance: Fully penetrant, with onset in neonates or in infancy
Nyctalopin Expression in Retinal Bipolar Cells Restores Visual Function in a Mouse Model of Complete X-Linked Congenital Stationary Night Blindness
PMID: 17881478
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.
Results
Case: IV-1
CasePresentingHPOsFreeText: Both affected subjects had symptoms of nonprogressive nyctalopia since childhood, while the proband also had photophobia. Both cases had a distance visual acuity of 20/50 or better in each eye, normal contrast sensitivity, and an incomplete type of Schubert-Bornschein ERGs. The proband also had high myopia, a mild red-green color deficit, hypopigmented fundus, and foveal hypoplasia with no evidence of chiasmal misrouting.
CasePreviousTesting:
CaseGenotypingMethod: Haplotype analysis was performed on all three members of the family using polymorphic microsatellite DNA markers flanking CACNA1F (DXS1003 and DXS7132. All exons and exon/intron boundaries of CACNA1F and nyctalopin (NYX) genes were sequenced in the proband (case IV 1)
Variant: c.1807G>C mutation (p.G603R)
ClinVarID: or CAID: CA412914688
gnomAD: not found in gnomAD v2.1.1
AddCaseInfo: The mutation is located on the S3 helical trans-membrane domain repeat II of the CACNA1F gene (CACNA1F encodes for the α1 subunit of a L-type Ca2+ channel that contains four repeat domains, each of which has six transmembrane domains (S1–S6); NP_005174.2). The p.G603R was predicted to be possibly damaging by Polyphen v. 2.09 with a PSIC score difference of 1.525. The mutation was predicted also to affect protein function by SIFT with a score of 0.00.
PreviouslyPublished:
The mouse ortholog of the neuronal ceroid lipofuscinosis CLN5 gene encodes a soluble lysosomal glycoprotein expressed in the developing brain
PMID: 15207259
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
variant
Case#: Holmberg_Patient_2, male, age 3 at onset and age 12 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 mental decline was present at age 3 and both visual deterioration and giant flash visual evoked potentials at age 6. Abolished ERG was found at age 7, and ataxia at age 8. Seizures and Loss of independent walking occurred at age 9. 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.1028_1029del (p.Thr342_Tyr343insTer) variant.
ClinVar: 2564 (homozygous)
gnomAD: The maximum allele frequency of the NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) variant is 0.0008137 (within the European Finnish population, with no homozygous occurrences). https://gnomad.broadinstitute.org/variant/13-77575052-CAT-C
VariantEvidence: NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer) is a recurring frameshift variant that is predicted to disrupt approximately 5% of CLN5 at the C-terminus and has been shown to disturb its localization to the lysosome (PMID:20052765).
CaseAddInfo: N/A
CasePMIDs: N/A
known
Case#: Holmberg_Patient_5, female, age 4 at onset and age 7 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: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: Age of onset was 4, while visual deterioration was found at age 6. Mental decline was found at age 7. 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
In mice, however, a null mutation in the GC1 gene produces a cone dystrophy; the GC1–/– rods remain viable and responsive to light (18Yang R.B. Robinson S.W. Xiong W.H. Yau K.W. Birch D.G. Garbers D.L. J. Neurosci. 1999; 19: 5889-5897Crossref PubMed Google Scholar, 19Coleman J.E. Zhang Y. Brown G.A. Semple-Rowland S.L. Investig. Ophthalmol. Vis. Sci. 2004; 45: 3397-3403Crossref PubMed Scopus (39) Google Scholar).
ExperimentName: Updated phenotypes from homozygous Gucy2e mouse knockout model
NonHumanModel: Mus musculus
GeneAlteration: The mouse Gucy2e gene was disrupted by the introduction of a neomycin-resistance gene cassette into exon 5, resulting in a truncated protein lacking its transmembrane domain (PMID: 10407028). The effects of this knockout were studied in both heterozygous and homozygous states.
ModelPhenotype: HP:0030465 (Undetectable light-adapted electroretinogram), HP:0030483 (Reduced amplitude of dark-adapted bright flash electroretinogram a-wave), HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0000479 (Abnormal retinal morphology)
HumanPhenotype: HP:0007663 (Reduced visual acuity), HP:0007688 (Undetectable light- and dark-adapted electroretinogram), HP:0007703 (Abnormality of retinal pigmentation)
ModelEvidence: This publication confirms previously-reported ERG abnormalities of rod and especially cone photoreceptors. The abnormal retinal morphology HPO term refers to abnormalities in the ultrastructure of the photoreceptor outer segment, which exhibited disorganization (Figures S2B, S2F, 8C, and 8E) and low GCAP1 and GCAP2 expression levels (Figures 5J and 5N), providing early signs of instability and degeneration.
ModelVariant: The mouse model disrupts the expression of the endogenous GC1 protein product but does not feature knock-in of a variant from a human patient.
Disruption of RPGR protein interaction network is the common feature of RPGR missense variations that cause XLRP
PMID: 30622176
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.
Four-point linkage analysis gave a maximum lod score of approximately 7.6 at both D8S1769 and GATA101H09 in the large consanguineous family. Recombination events defined an interval of 8.7 cM between D8S1820 and D8S532 within which the gene must lie. This 8p11 locus (CORD9) is immediately distal to but distinct from the RP1 autosomal dominant RP (adRP) locus.
FamilyLabel: Danciger_2001_Family
Family#PresentingHPOs: HP:0011463 (Childhood onset), HP:0007663 (Reduced visual acuity), HP:0001141 (Severely reduced visual acuity), HP:0007994 (Peripheral visual field loss), HP:0000545 (Myopia), HP:0000483 (Astigmatism), HP:0000523 (Subcapsular cataract)
FamilyPresentingHPOFreeText: The affected family members have been diagnosed with severe cone-rod dystrophy segregating with an autosomal recessive mode of inheritance.
FamilyNotHPOs: N/A
FamilyNotHPOFreeText: N/A
CountryOrigin: Brazil
Ethnicity: Brazilian
Race: Not described
Family#PreviousTesting: Linkage mapping has been performed in affected and unaffected family members using short tandem repeat markers across the genome.
Family#Method1: Linkage mapping using short tandem repeat markers
Family#Method2: Haplotype analysis with markers within an 8-cM region of chromosome 8p11.
Family#GenotypingMethod: Linkage mapping has been performed in affected and unaffected family members using short tandem repeat markers across the genome, followed by haplotype analysis within the linkage region. A subsequent publication sequenced 10 out of 34 genes within the linkage region and found homozygous variants in ADAM9 in particular (PMID: 19409519).
Affected: 5
Unaffected: 7
Segregations: 7 segregations are shown by the pedigree in Figure 1.
PublishedLOD: 7.6 (associated with the D8S1769 and GATA101H09 short tandem repeat markers on chromosome 8p11)
eLOD: N/A
AddSegregationInfo: N/A
ProbandLabel: Danciger_2001_Family_Patient_A
Variant: The affected family members harbor the NM_003816.3(ADAM9):c.1130+1G>A variant in the homozygous state.
ClinVar: 6876
gnomAD: This variant was not found in gnomAD v2.1.1.
VariantEvidence: The NM_003816.3(ADAM9):c.1130+1G>A variant is predicted to disrupt a canonical splice site in intron 11.
FamilyAddInfo: The family is known to be consanguineous, with the parents of affected individuals being second cousins.
FamilyPMIDs: PMID: 19409519
family 1002, direct genomic sequencing was performed on the amplified exon 4 fragment from the proband
Case#: Family 1002, Greek, 26 years, now living in USA.
CaseHPOs:
CaseHPOsFreeText: Difficulty adapting to the dark from early childhood. Fundus exam (see Fig 2A) at age 26 years showed yellow-white dots, sharply demarcated, sparing the macula and radiating from the perimacular region; well-defined foveal reflex, absent pigmentary changes, normal vascular caliber.
CaseNotHPOsFreeText: No other associated ocular or systemic disorders.
CasePreviousTesting: RBP3 excluded by heteroduplex analysis and sequencing (this study). Affected siblings had non-concordant pattern for an intragenic RFLP analyzed by Southern blot.
CaseMethod1: SSCP
CaseMethod2: Sanger sequencing
Variant: c.712G>T (p.Gly238Trp) (homozygous)
ClinVar: 8003
CAID: CA119196
gnomAD: The highest population MAF in gnomAD v2.1.1 is 0.0004532 (Latino/Admixed American); no homozygotes in any population.
CaseAddInfo: Parents are seventh cousins
Not scoring because another patients with this genotype has already been included.
Combining a prioritization strategy and functional studies nominates 5'UTR variants underlying inherited retinal disease
PMID: 38184646
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).
Visually impaired rhesus macaques show signs of achromatopsia.
ExperimentName: This macaque model harbors a homozygous loss-of-function variant in PDE6C.
NonHumanModel: Macaca mulatta
GeneAlteration: The model animals are homozygous for a missense variant, p.Arg565Gln, which is shown to cause a decrease in enzymatic activity.
ModelPhenotype: HP:0007663 (Reduced visual acuity, particularly in well illuminated settings where unaffected animals led them by the hand), HP:0001483 (Eye poking), HP:0030465 (Undetectable light-adapted electroretinogram), normal dark-adapted ERG, HP:0007401 (Macular atrophy), HP:0011504 (Bull's eye maculopathy), HP:0030619 (Reduced OCT-measured foveal thickness), HP:0030610 (Photoreceptor outer segment loss on macular OCT), HP:0030609 (Photoreceptor layer loss on macular OCT)
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 macaque model that matches the autosomal recessive mode of inheritance from the human patients (Figure 7) and exhibits reduced visual acuity (Supplemental Video 1), lack of light-adapted ERG responses and normal dark-adapted ERG responses (Figures 1A-1E, Figure 2). The affected animals also exhibit progressive macular atrophy consistent with achromatopsia (Figure 3). Reduced foveal thickness was also observed (Figures 4A, 4B), as well as thinning of the outer nuclear layer and photoreceptor outer segments (Figures 5A, 5B).
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 PDE6C locus.
In MOL0277, a homozygous intronic change (c.411-8A→G) was the only potentially pathogenic change identified. Sequence of cDNA derived from patients' peripheral blood lymphocyte mRNA demonstrated that this mutation activated a cryptic splice acceptor site giving rise only to an aberrant transcript (Figure 2B). The mutant transcript has seven additional base pairs of sequence added to the beginning of exon 6 and is predicted to introduce a frameshift resulting in premature termination (R137SfsX16).
Case#: Parry_2009_Family_MOL0277_patient_IV:2, male, age not specified, family origin reported to be Arab Muslim
CasePresentingHPOs: HP:0410280 (Pediatric onset), HP:0007663 (Reduced visual acuity), HP:0007401 (Macular atrophy), HP:0000580 (Pigmentary retinopathy), HP:0007769 (Peripheral retinal degeneration), HP:0008323 (Abnormal light- and dark-adapted electroretinogram)
CaseHPOFreeText: The proband was diagnosed with cone-rod dystrophy, with family showing autosomal recessive mode of inheritance. Most affected members of the proband's family had white patches around the optic disc and in the posterior pole.
CaseNotHPOs: HP:0000639 (Nystagmus), HP:0000613 (Photophobia)
CaseNotHPOFreeText: N/A
CasePreviousTesting: The proband and his family have been initially genotyped by autozygosity mapping with both 10k and 250k Affymetrix SNP arrays and microsatellite markers.
CaseMethod1: Autozygosity mapping
CaseMethod2: Sanger sequencing
CaseGenotypingMethod: The proband and his family have been initially genotyped by autozygosity mapping with both 10k and 250k Affymetrix SNP arrays and microsatellite markers. Sanger sequencing of the ADAM9 locus then identified the variants.
Variant: The proband harbors the NM_003816.3(ADAM9):c.411-8A>G variant in the homozygous state.
ClinVar: 6879
gnomAD: This variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_003816.3(ADAM9):c.411-8A>G is a variant in intron 5 that has been shown to trigger aberrant splicing and abolish normal splicing by activating use of a cryptic splice acceptor site (Figure 2B). The predicted result is to add 7 bp to the 5' end of exon 6 and introduce a frameshift causing premature termination. Since this affects exon 6 of 21, the predicted result is nonsense-mediated decay or truncation of the C-terminal 83% of the protein product (p.Arg137SerfsX16).
CaseAddInfo: The proband's family is known to be consanguineous, with the parents being first cousins (pedigree shown in Figure 2).
CasePMIDs: N/A
The retinal pigment epithelium in Sorsby Fundus Dystrophy shows increased sensitivity to oxidative stress-induced degeneration
PMID: 32828705
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
65 + 5G-->A
Case#: Gu_1997_Patient_arRP181-II-1, female, 45, German ethnicity
CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0000572 (Visual loss), HP:0410280 (Pediatric onset), HP:0000546 (Retinal degeneration), HP:0000618 (Blindness)
CaseHPOFreeText: Visual loss had onset in childhood. Retinal degeneration was diagnosed at age 10. Legal blindness was found at age 18.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous testing was limited to clinical diagnosis of arRP.
CaseMethod1: PCR amplification and Sanger sequencing
CaseMethod2: N/A
CaseGenotypingMethod: RPE65 was subjected to PCR amplification and Sanger sequencing.
Variant: The patient is homozygous for the NM_000329.3(RPE65):c.11+5G>A variant.
ClinVar: 98825 (homozygous)
gnomAD: The maximum allele frequency of the NM_000329.3(RPE65):c.11+5G>A variant is 0.0001626 (in the European non-Finnish population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68915573-C-T
VariantEvidence: The variant is located within intron 1 of the RPE65 transcript and affects part of the splice donor consensus sequence. SpliceAI calculates a delta score of 0.06 for loss of splice donor site.
CaseAddInfo: Consanguinity of the parents is not proven but considered possible due to their origin from the same village. One of the patient's three siblings is affected (similarly or more severely), but none have been genotyped.
CasePMIDs: N/A
Mutations in RPE65 cause autosomal recessive childhood-onset severe retinal dystrophy
PMID: 9326941
Gene: RPE65
HGNC: 10294
Disease: Retinitis pigmentosa 20
MONDO: 0013425
InheritancePattern: Autosomal Recessive
Prevalence: The overall prevalence of Retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of recessive Retinitis pigmentosa caused by RPE65 variants is ~2%. (PMID: 9501220) Thus, the prevalence of Retinitis pigmentosa 20 is between 1 in 150,000 and 1 in 200,000.
Penetrance: Fully penetrant, with onset typically in childhood
Cloning of the gene for ocular albinism type 1 from the distal short arm of the X chromosome
PMID: 7647783
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.
RP1L1 variants are associated with a spectrum of inherited retinal diseases including retinitis pigmentosa and occult macular dystrophy
PMID: 23281133
Gene: RP1L1
HGNC: 15946
Disease: occult macular dystrophy
MONDO: 0013316
InheritancePattern: autosomal dominant
Prevalence: The prevalence of occult macular dystrophy is "significantly less than one in 10,000 or 100,000 (https://www.reviewofoptometry.com/article/the-best-is-yet-to-come-feb).
Penetrance: The disease is known to be incompletely penetrant in family members carrying the heterozygous p.Arg45Trp variant (PMID: 20826268).
Background
Case: Case_47
CasePresentingHPOsFreeText: RP, A cohort of 168 unrelated Korean patients with IRD was recruited from the Department of Ophthalmology, Seoul National University Hospital (SNUH), from October 2008 to January 2019. A detailed family history was obtained from each patient to construct a pedigree. All patients underwent a detailed ophthalmic history and ophthalmic examinations, including best-corrected visual acuity, slit-lamp biomicroscopy, fundus photography, optical coherence tomography, fluorescein angiography, visual field tests, and full-field electroretinograms. Clinical diagnosis was determined by at least two retinal specialists (DJM and UCP).
CasePreviousTesting: WES
CaseGenotypingMethod: WES was performed at the Genomics core facility of the Center for BioMarkers (SNUH, South Korea) using an Illumina NextSeq500
Variant: c.2514_2515del, p.N838fs
ClinVarID: or CAID: CA2573335125
gnomAD:
AddCaseInfo:
PreviouslyPublished:
VariantEvidence:
Whole-exome sequencing in 168 Korean patients with inherited retinal degeneration
PMID: 33691693
Gene: TOPORS
novel mutation
Case#: Corton_2010_Family_RP-72_patient_IV:2, male, age 35 years at time of study, age 6 at onset, Spanish family origin from Galicia
CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0000540 (Hypermetropia), HP:0007663 (Reduced visual acuity), HP:0030526 (Severe constriction of peripheral visual field), HP:0000550 (Undetectable electroretinogram), HP:0007737 (Bone spicule pigmentation of the retina), HP:0007401 (Macular atrophy), HP:0007843 (Attenuation of retinal blood vessels), HP:0000543 (Optic disc pallor)
CaseHPOFreeText: The proband and his affected family members have been diagnosed with autosomal recessive retinitis pigmentosa.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Haplotype analysis was initially performed in the patient and his affected family members.
CaseMethod1: Haplotype analysis
CaseMethod2: Sanger sequencing of PDE6A, PDE6B, and RHO
CaseGenotypingMethod: Haplotype analysis was initially performed in the patient and his affected family members, showing shared regions of homozygosity in the PDE6A, PDE6B, and RHO genes. Sanger sequencing was then performed on PCR products of exons and flanking regions from these three loci.
Variant: The proband harbors the NM_000440.3(PDE6A):c.2053G>A (p.Val685Met) variant in the homozygous state.
ClinVar: 29874
gnomAD: In gnomAD v2.1.1, NM_000440.3(PDE6A):c.2053G>A (p.Val685Met) has a frequency of 0.00008531 (11/128938) in the European non-Finnish population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/5-149263074-C-T
VariantEvidence: A mutation equivalent to this variant in the homozygous nmf28/nmf28 mouse model caused grainy abnormalities in fundus pigmentation associated with loss of most photoreceptor cells shortly after birth, as well as loss of cGMP-PDE6 activity resulting in increased intracellular cGMP levels (PMID: 18849587).
CaseAddInfo: The proband is from a family with multiple consanguineous unions and three affected paternal aunts.
CasePMIDs: N/A
Next-Generation Sequencing–Based Molecular Diagnosis of a Chinese Patient Cohort With Autosomal Recessive Retinitis Pigmentosa
PMID: 23661369
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.
In the IMPG2 mutant, a 7 nt deletion in exon 3 led to a premature termination on the same exon. In both cases, we expected nonsense-mediated decay and consequent loss of IMPG1 and IMPG2 proteins (Fig. 2A). The IHC analysis confirmed the absence of IMPG1 or IMPG2 proteoglycans in IMPG1 and IMPG2 KO mice, respectively.
ExperimentName: CRISPR/Cas9-based disruption of mouse Impg2
NonHumanModel: Mus musculus
GeneAlteration: Model animals were subjected to CRISPR/Cas9-based deletion of 7bp from exon 3 of Impg2, and analyzed in the homozygous state. Absence of Impg2 signal was confirmed by immunofluorescent staining. Mice were studied at ages 5 months and 8 months.
ModelPhenotype: HP:0030612 (Abnormal retinal morphology, specifically mislocalization / scattering of IMPG1 throughout the outer segment and at the boundary with the RPE), HP:0030643 (Vitelliform-like subretinal lesions), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude)
HumanPhenotype: HP:0000529 (Progressive visual loss), HP:0000662 (Nyctalopia), HP:0000551 (Color vision defect), HP:0008002 (Abnormality of macular pigmentation), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0000533 (Chorioretinal atrophy), HP:0000518 (Cataract), HP:0008323 (Abnormal light- and dark-adapted electroretinogram), HP:0007737 (Bone spicule pigmentation of the retina), HP:0007994 (Peripheral visual field loss), HP:0000603 (Central scotoma)
ModelEvidence: This is the first mouse model of Impg2 disruption, with confirmed absence of Impg2 in the homozygous animals. Abnormalities included mislocalization of Impg1 and the cone-specific marker Pna (Figure 2), accumulation of anomalous material between the photoreceptor outer segment and RPE (Figure 3), development of subretinal hyper-reflective vitelliform lesions (Figure 4), and reduction in the amplitudes of ERG responses from both rods (Figure 5A) and cones (Figure 5B).
ModelVariant: The model does not introduce a variant previously observed in human patients, but rather disrupts the expression of the Impg2 ortholog.
Sequence of a patient carrying the CLN5 Fin major mutation, (AT)2467 deletion.
Case#: Savukoski_Fin_Major_Patient_1, no demographic details, Finnish origin
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous testing relied on linkage analysis using PCR-amplifiable polymorphisms, including microsatellite markers. The marker D13S160 was found to co-segregate with disease with a LOD score of 4.78 across 14 Finnish pedigrees, mapping the disease locus to chromosome 13q21.1-q32 (PMID:7942847). A follow-up study used two additional microsatellite markers to map the locus to a 200-kb region (PMID:8661106), which was then analyzed in the present study and found to contain a single coding gene.
CaseMethod1: Linkage analysis using PCR-amplifiable polymorphisms, including microsatellite markers, followed by more detailed linkage analysis using two additional microsatellite markers to map the locus to a smaller 200-kb region (PMID:8661106).
CaseMethod2: N/A
CaseGenotypingMethod: PCR products from the four exons of CLN5 were generated from the affected individual and a control individual and subjected to Sanger sequencing. Genome-wide analysis methods were not used.
Variant: Patient is homozygous for NM_006493.4(CLN5):c.1028_1029del (p.Thr342_Tyr343insTer), although this variant is referred to in the article as (AT)2467del.
ClinVar: 2564
gnomAD: The variant is reported to have a maximum allele frequency of 0.0008137 (in the European Finnish population, with no homozygous individuals). https://gnomad.broadinstitute.org/variant/13-77575052-CAT-C
VariantEvidence: This frameshift variant is expected to truncate 16 amino acids from the C-terminus of CLN5 (between 4-5% of the total polypeptide), without triggering NMD. However, it abolishes an N-glycosylation site (PMID:24058541). This may explain why it fails to localize to large endosomes but rather is retained within the ER, possibly indicating improper folding (PMID:24058541). It also exhibits reduced stability relative to other variants (PMID:24058541).
CaseAddInfo: N/A
CasePMIDs: PMID:7942847, PMID:8661106
Sequence of a Dutch patient with the CLN5 European mutation, a G2127→A transversion.
Case#: Savukoski_European_Patient_1, no demographic details, Dutch origin
CasePresentingHPOs: N/A
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
CaseMethod1: N/A
CaseMethod2: N/A
CaseGenotypingMethod: PCR products from the four exons of CLN5 were generated from the affected individual and a control individual and subjected to Sanger sequencing. Genome-wide analysis methods were not used.
Variant: Patient is homozygous for NM_006493.4(CLN5):c.688G>A (p.Asp230Asn), although this variant is referred to in the article as c.G2127A or p.Asp279Asn.
ClinVar: 2566
gnomAD: The variant is reported to have a maximum allele frequency of 0.00005437 (in the East Asian population, with no homozygous individuals). https://gnomad.broadinstitute.org/variant/13-77574715-G-A
VariantEvidence: This missense variant in the fourth / final exon is predicted to introduce an additional N-glycosylation site within the C-terminal region of CLN5. Slower electrophoretic migration of the exogenously expressed protein indicates that the abnormal N-glycosylation site is functional (PMID:20052765). The variant also disturbs lysosomal trafficking (PMID:20052765).
CaseAddInfo: N/A
CasePMIDs: N/A
The Benign Concentric Annular Macular Dystrophy Locus Maps to 6p12.3-q16
PMID: 14691150
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.
Eyes shut homolog (EYS) interacts with matriglycan of O-mannosyl glycans whose deficiency results in EYS mislocalization and degeneration of photoreceptors
PMID: 32385361
Gene: EYS
HGNC: 21555
Disease: Retinitis pigmentosa 25
MONDO: MONDO:0011272
InheritancePattern: autosomal recessive
Prevalence: The overall prevalence of retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of retinitis pigmentosa caused by homozygous or compound heterozygous EYS variants is estimated to be 12% in the French population (PMID: 20333770), implying in an overall prevalence between 1 in 25,000 and 1 in 33,000.
Penetrance: The disease appears to be completely penetrant among published families.
Photoreceptor peripherin is the normal product of the gene responsible for retinal degeneration in the rds mouse
PMID: 1992463
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).
Systemic splicing factor deficiency causes tissue-specific defects: a zebrafish model for retinitis pigmentosa
PMID: 21051334
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).
P3-ES; II.3
Case#:P3-ES; II.3, F, Age of report: 58 y.o., Ethnicity: Spanish.
CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy/Retinitis pigmentosa), HP:0005101 (High-frequency hearing impairment/non-progressive hearing loss at high frequencies), HP:0000543 (Optic disc pallor/pale optic disc), HP:0500081 (Pseudophakia), HP:0012832 (Bilateral),
CaseHPOFreeText: F3 is a consanguineous family (parents are second cousins) of Spanish origin with three affected and two unaffected siblings (Fig. 1c).
The index case (P3-ES; II.3) is a 58 years-old female with a typical RP and a late-onset, moderate, non-progressive hearing loss at high frequencies (Fig. 3). She had a BCVA of 0.3 D with a 10° central visual field in either eye, and presented a typical RP fundus with a pale optic disc, vessel attenuation, and pigment deposits in the periphery (with alterations of the RPE at the macular area). She had bilateral pseudophakia and did not present CME (Table 2).
CaseNotHPOs: N/A.
CaseNotHPOFreeText: N/A.
CasePreviousTesting: N/A.
CaseMethod1: N/A.
CaseMethod2: N/A.
CaseGenotypingMethod: Custom panel of 117 genes associated with IRDs and WES.
Variant: Variant 1: NM_021831.6:c.1565del (p.Gly522AspfsTer4). Variant 2: NM_021831.6:c.908G>A (p.Arg303His).
ClinVar: Variant 1: N/A. Variant 2: 1044022.
CAID: Variant 1: CA3051368245. Variant 2: CA1567753.
gnomAD: Variant 1: N/A. Variant 2: Frequency: 0.00001995. Link: https://gnomad.broadinstitute.org/variant/chr2-27055253-G-A?dataset=gnomad_r4.
VariantEvidence: N/A.
CaseAddInfo: The proband's affected brothers were not collaborative for clinical examination in this study, but the proband referred that her elder brother (II.1) uses hearing aids and her younger brother (II.5) has a mild hearing impairment, both presenting also RP. Her unaffected siblings (II.2, II.4) do not present RP or hearing impairment. The three affected members were initially referred for genetic testing in 2015 with a clinical diagnosis of isolated RP. One of them (II.3, P3-ES) was analysed using a custom panel of 117 genes associated with IRDs, but no pathogenic variants were identified [27]. Subsequently, WES performed in two affected siblings (II.3, II.5) revealed compound heterozygous pathogenic variants in AGBL5 (Table 1) which segregated with the disease in the family (Fig. 1c).
CasePMIDs: N/A.
Interactions within the Coiled-coil Domain of RetGC-1 Guanylyl Cyclase Are Optimized for Regulation Rather than for High Affinity
PMID: 11306565
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.
Haplotype reconstruction in three SFD families revealed that the identified c.113C>G, p.(Ser38Cys) mutation is a founder in Belgian and northern French families with a late-onset SFD phenotype.
GroupName: Naessens_2019_Group
GroupPresentingHPOs: HP:0011510 (Drusen)
GroupHPOFreeText: Relatively late onset of phenotypes between ages 49 and 74. Drusen / deposits were universal except for 3 individuals between the ages of 37 and 47.
GroupNotHPOs: N/A
GroupNotHPOFreeText: pulmonary involvement
GroupDemographics
NumberMales: 13
NumberFemales: 9
CountryOrigin: Belgium (Families 1 and 3) or northern France (Family 2)
Ethnicity: Not mentioned
Race: Not mentioned
AgeRange: The individuals mentioned range in age from 51 to 74 years, although other unmentioned individuals may be older or younger.
TotalNumber: 22
FamilyInfo: 21
NoFamily: 1
VariantCount: 22
NonVariant: 0
OtherVariant: N/A
GroupPreviousTesting: N/A
GroupGenotypingMethod: PCR amplification of all 5 coding exons of TIMP3, followed by Sanger sequencing
SPACR Encoded by IMPG1 Is Essential for Photoreceptor Survival by Interplaying between the Interphotoreceptor Matrix and the Retinal Pigment Epithelium
PMID: 36140676
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.
Peripherin mutations cause a distinct form of recessive Leber congenital amaurosis and dominant phenotypes in asymptomatic parents heterozygous for the mutation
PMID: 26061163
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).
(https://eyeintegration.nei.nih.gov/)
Selection A - Gene is expressed in tissues relevant to disease:
ExperimentName: High GUCY2D mRNA expression in human retina relative to other tissue types
TissueExpression: Retina (UBERON:0000966)
ExpressionEvidence: Evidence can be accessed on the publication-associated website (https://eyeintegration.nei.nih.gov/) through the Pan-Tissue Plots feature.
CLN5 and CLN8 protein association with ceramide synthase: biochemical and proteomic approaches
PMID: 23160995
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
488
Case#: Bravo-Gil_2016_Proband_488, sex not specified, onset at birth, family origin reported as Spanish
CasePresentingHPOs: HP:0000618 (Blindness), HP:0001133 (Constriction of peripheral visual field), and HP:0000662 (Nyctalopia), HP:0003577 (Congenital onset), HP:0000639 (Nystagmus), HP:0010442 (Polydactyly). HP:0001249 (Intellectual disability), HP:0001513 (Obesity)
CaseHPOFreeText: The proband is part of an inherited retinal disease cohort and received an initial diagnosis of Bardet-Biedl syndrome. Reduced visual acuity was the first visual symptom. The patient is now described as having total blindness.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: The proband was genotyped by a capture-based next-generation sequencing panel that included 64 known retinal genes.
CaseMethod1: next-generation sequencing panel
CaseMethod2: Sanger sequencing of BBS1 to validate the presence of the variants
CaseGenotypingMethod: The proband was genotyped by a capture-based next-generation sequencing panel that included 64 known retinal genes, followed by Sanger sequencing of BBS1 to validate the presence of the variants.
Variant: The proband harbors the NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) and NM_024649.5(BBS1):c.118del (p.Cys40fs) variants in the compound heterozygous state.
ClinVar ID: 12143, 802688
gnomAD: The NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) variant is found in gnomAD v2.1.1 at a frequency of 0.002773 in the European (non-Finnish) population, with 358 alleles / 129114 total alleles (0 homozygotes) https://gnomad.broadinstitute.org/variant/11-66293652-T-G?dataset=gnomad_r2_1 The NM_024649.5(BBS1):c.118del (p.Cys40fs) variant is found in gnomAD v2.1.1 at a frequency of 0.00005782 (2 alleles / 34592 total alleles, with 0 homozygotes) in the Admixed American population https://gnomad.broadinstitute.org/variant/11-66278553-CT-C?dataset=gnomad_r2_1
VariantEvidence: NM_024649.5(BBS1):c.1169T>G (p.Met390Arg) is a missense variant with mouse knock-in evidence of a similar disease-causing effect in the homozygous state (PMID: 18032602). This has not been taken into account in scoring, as the mouse model has been scored separately. However, it has provided a rationale not to down-score for the relatively high gnomAD frequency of this variant. NM_024649.5(BBS1):c.118del (p.Cys40fs) is a frameshift variant in exon 2 of 17 that is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 93% of the protein product.
CaseAddInfo: The proband's family has not been described as consanguineous.
CasePMIDs: N/A
BBS7
Case#: Solmaz_2015_Proband_9, male, age 19 years at time of report, part of cohort from Turkey
CasePresentingHPOs: HP:0031418 (Increased body mass index), HP:0000510 (Rod-cone dystrophy), HP:0000750 (Delayed speech and language development), HP:0000218 (High palate), HP:0000678 IDental crowding), HP:0010442 (Polydactyly), HP:0001159 (Syndactyly), HP:0001156 (Brachydactyly), HP:0000026 (Male hypogonadism), HP:0001256 (Intellectual disability, mild)
CaseHPOFreeText: The patient has been diagnosed with Bardet-Biedl syndrome.
CaseNotHPOs: HP:0000365 (Hearing impairment), HP:0000077 (Abnormality of the kidney)
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous genotyping consisted of an NGS-based panel focusing on the BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, TRIM32, BBS12, MKS1, CEP290, WDPCP, SDCCAG8, NPHP1 loci.
CaseMethod1: NGS-based panel focusing on the BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, TRIM32, BBS12, MKS1, CEP290, WDPCP, SDCCAG8, NPHP1 loci.
CaseMethod2: Sanger sequencing of the BBS7 locus
CaseGenotypingMethod: Genotyping consisted of an NGS-based panel focusing on the BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, TRIM32, BBS12, MKS1, CEP290, WDPCP, SDCCAG8, NPHP1 loci, followed by Sanger sequencing of the BBS7 locus.
Variant: The patient harbors the NM_018190.4:c.712_715del (p.Arg238GlufsTer59) variant in the homozygous state.
CAID: CA3064432
gnomAD: The NM_018190.4:c.712_715del (p.Arg238GlufsTer59) variant is found in gnomAD v2.1.1 at a maximum allele frequency of 0.0001146 (13/113390) in the European non-Finnish population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/4-122775861-CCTCT-C
VariantEvidence: NM_018190.4:c.712_715del (p.Arg238GlufsTer59) 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 65% of the protein product.
CaseAddInfo: Consanguinity of this specific patient's family is unknown, but the cohort was reported to have a high rate of consanguineous probands.
CasePMIDs: N/A
Gene therapy was performed on adult squirrel monkeys (Saimiri sciureus) that were missing the L opsin gene. In this species, some females have trichromatic colour vision while males are red-green colour blind2.
ExperimentName: Colorblind squirrel monkeys were rescued by human OPN1LW.
NonHumanModel: Saimiri sciureus
GeneAlteration: Male squirrel monkeys were missing OPN1LW gene. Controls with the intact gene were not part of the study.
RescueVariant: Rescue was performed by subretinal injection of recombinant adeno-associated virus containing human OPN1LW under control of the appropriate enhancer and promoter and featured the wild-type gene rather than a variant.
RescuePhenotype: The rescued phenotypes are inability to discriminate between blue and green wavelengths to obtain a food reward and defects in performance on a computer-administered Cambridge colour test.
RescueMethod: This rescue model has injection of recombinant adeno-associated virus containing human wild-type OPN1LW under control of the appropriate enhancer and promoter.
RescueEvidence: Squirrel monkeys gained the ability to discriminate between blue and green wavelengths to obtain a food reward (data not shown), as well as significant improvement in ability to distinguish colors occurring at ~20 weeks post-injection (Figure 3A). Gaps in the ability to detect certain wavelengths pre-injection (solid lines) were filled in post-injection (dotted lines) in monkey 1 (Panel 3B) and monkey 2 (Panel 3C). These confirmed that monkeys had become trichomatic and matched the new ability to access food rewards.
ModelVariant: The model does not include any human OPN1LW variant, only the wild-type gene.
We demonstrate that the 60 and 90kD tri-snRNP proteins specifically associate with the U4/U6 snRNP at salt concentrations where the tri-snRNP complex has dissociated. The primary structures of the 60kD and 90kD proteins were determined by cloning and sequencing their respective cDNAs. The U4/U6-60kD protein possesses a C-terminal WD domain that contains seven WD repeats and thus belongs to the WD-protein family, whose best-characterized members include the Gbeta subunits of heterotrimeric G proteins. A database homology search revealed a significant degree of overall homology (57.8% similarity, 33.9% identity) between the human 60kD protein and the Saccharomyces cerevisiae U4/U6 snRNP protein Prp4p. Two additional, previously undetected WD repeats (with seven in total) were also identified in Prp4p, consistent with the possibility that 60kD/Prp4p, like beta-transducin, may adopt a propeller-like structure. The U4/U6-90kD protein was shown to exhibit significant homology, particularly in its C-terminal half, with the S. cerevisiae splicing factor Prp3p, which also associates with the yeast U4/U6 snRNP. Interestingly, U4/U6-90kD shares short regions of homology with E. coli RNase III, including a region encompassing its double-stranded RNA binding domain. Based on their structural similarity with essential splicing factors in yeast, the human U4/U6-60kD and 90kD proteins are likely also to play important roles in the mammalian splicing process.
Selection A- Gene with same function implicated in disease
ExperimentName: PRPF4 is a U4/U6 small nuclear ribonucleoprotein component that functions in mRNA splicing.
GOterm: GO:0000398 (mRNA splicing, via spliceosome)
FunctionalEvidence: PRPF4, PRPF3, PRPF31, and PRPF8 are all splicing factors involved in mRNA processing and are encoded by genes that harbor variants associated with retinitis pigmentosa.
HGNC: HGNC:17348 (PRPF3, retinitis pigmentosa 18), HGNC:15446 (PRPF31, retinitis pigmentosa 11), HGNC:17340 (PRPF8, retinitis pigmentosa 13)
GeneEvidence: PRPF3 harbors variants that cause retinitis pigmentosa 18 (PMID: 11773002), PRPF31 harbors variants that cause retinitis pigmentosa 11 (PMID: 12444105), and PRPF8 harbors variants that cause retinitis pigmentosa 13 (PMID: 7951236).
SharedGeneImplication: PRPF4, PRPF3, PRPF31, and PRPF8 are encode splicing factors involved in mRNA processing.
V.1
Case: Gliem_2000_Family_2_patient_V.1, male, country of origin Germany, onset at 51 years of age
DiseaseAssertion: Sorsby fundus dystrophy
FamilyInfo: The variant was inherited by the proband rather than acquired de novo.
CasePresentingHPOs: HP:0007663 (Reduced visual acuity), HP:0011510 (Drusen), HP:0000533 (Chorioretinal atrophy), HP:0012508, (Metamorphopsia), HP:0000662 (Nyctalopia)
CaseHPOFreeText: Presentation at age 51 with visual loss. Evaluation at age 71 found widespread central and midperipheral chorioretinal atrophy, thinning of the choroid in areas of atrophy, central focal subretinal fibrosis at the posterior pole, metamorphopsia (with onset in the sixth decade of life), and nyctalopia that was only developed late in disease progression.
CaseNOTHPOs: N/A
CaseNOTHPOFreeText: N/A
CasePreviousTesting: Phenotypic characterization only
GenotypingMethod: Sanger sequencing of PCR products from all 5 exons and flanking splice junctions of the TIMP3 gene.
PreviouslyPublished: 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.
SupplementalData: N/A
Variant: Patients harbor the NM_000362.5(TIMP3):c.545A>G (p.Tyr182Cys) missense variant.
CAID: CA411540365
gnomAD: Variant is absent from gnomAD.
VariantEvidence: This missense variant within exon 5 of TIMP3 results in an unpaired Cys residue.
F5-P9,10,11PRSS56: c.[1066dupC];[1066dupC],p.[Gln356ProfsX152];[Gln356ProfsX152
Case#: Gal_2011_Family_5_Proband_P9, female, age 21 years at time of report, family national origin described as Saudi
CasePresentingHPOs: Hypermetropia HP:0000540, Microphthalmia HP:0000568
CaseHPOFreeText: The proband received a diagnosis of posterior microphthalmos, with one feature being a moderate papillomacular fold.
CaseNotHPOs: Ocular hypertension HP:0007906
CaseNotHPOFreeText: N/A
CasePreviousTesting: The proband's family may have been previously subjected to linkage mapping, and was also previously genotyped by Sanger sequencing of the MFRP locus.
CaseMethod1: Sanger sequencing of MFRP
CaseMethod2: Sanger sequencing of PRSS56
CaseGenotypingMethod: The proband's family may have been previously subjected to linkage mapping, and was also previously genotyped by Sanger sequencing of the MFRP locus, followed by Sanger sequencing of PRSS56.
Variant: The individual harbors the NM_001195129.2(PRSS56):c.1066dup (p.Gln356fs) variant in the homozygous state.
ClinVar: 31077
gnomAD: This variant is found in gnomAD v4.1.0 at a frequency of 0.0008496 in the Middle Eastern population https://gnomad.broadinstitute.org/variant/2-232523817-A-AC?dataset=gnomad_r4
VariantEvidence: NM_001195129.2(PRSS56):c.1066dup (p.Gln356fs) is a frameshift variant in exon 9 of 13 and is predicted to trigger nonsense-mediated decay.
CaseAddInfo: The proband is from a cohort where more than half of the families had known consanguinity.
CasePMIDs: N/A
RPE65 is the isomerohydrolase in the retinoid visual cycle
PMID: 16116091
Gene: RPE65
HGNC: 10294
Disease: Leber congenital amaurosis 2
MONDO: 0008765
InheritancePattern: Autosomal Recessive
Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns, while the proportion of Leber congenital amaurosis caused by RPE65 variants is between 1% and 16.7%. Thus, the prevalence of Leber congenital amaurosis 2 is between 1 in 200,000 and 1 in 10,000,000.
Penetrance: Fully penetrant, with onset typically by 1 year of age
The JATD1 patient was notable for having had severe kidney involvement requiring kidney transplant during childhood, as well as retinal disease, as detailed in Table 1. In addition, typical skeletal features of JATD were present in this patient (Fig. 1A, F, and L). We proceeded to screen additional patients using a diagnostic NGS panel developed for ciliopathies encompassing all exons and adjacent intronic boundaries of 131 known ciliopathy genes. This totaled 2,412 coding exons of genes selected from cilia proteome and ciliary trafficking studies (Frank et al., 2012).
Case#: Schmidts_2013_Patient_JATD1, male, 12 years of age at time of study, of Serbian ethnicity
CasePresentingHPOs: HP:0003593 (Infantile onset), HP:0002093 (Respiratory insufficiency), HP:0000556 (Retinal dystrophy), HP:0009370 (Type A brachydactyly), HP:0004322 (Short stature), HP:0005257 (Thoracic hypoplasia), HP:0010579 (Cone-shaped epiphysis), HP:0000369 (Low-set ears), HP:0003774 (Stage 5 chronic kidney disease), HP:0007703 (Abnormality of retinal pigmentation), HP:0000803 (Renal cortical cysts), HP:0033130 (Abnormal renal echogenicity), HP:0000822 (Hypertension), HP:0000773 (Short ribs), HP:0000900 (Thickened ribs), HP:0000774 (Narrow chest)
CaseHPOFreeText: This proband was diagnosed with Jeune's asphyxiating thoracic dystrophy (JATD).
CaseNotHPOs: HP:0010442 (Polydactyly), HP:0001737 (Pancreatic cysts), HP:0001392 (Abnormality of the liver), HP:0001263 (Global developmental delay)
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous testing appears to have been limited to a clinical diagnosis of Jeune's asphyxiating thoracic dystrophy.
CaseMethod1: Whole exome sequencing, focusing on variants consistent with autosomal recessive inheritance and homologous to genes present in the ciliary proteome.
CaseMethod2: Sanger sequencing of IFT140 in the patient and available family members
CaseGenotypingMethod: The patient and family members were genotyped by whole exome sequencing and confirmed by Sanger sequencing of IFT140.
Variant: The patient is a compound heterozygote harboring the paternal NM_014714.4(IFT140):c.874G>A (p.Val292Met) and maternal NM_014714.4(IFT140):c.1380del (p.Asn460fs) variants in IFT140.
ClinVar ID: 97053, 97055
gnomAD: The NM_014714.4(IFT140):c.874G>A (p.Val292Met) variant is present in gnomAD at a frequency of 0.000008852 in the European non-Finnish population (1/112966, with no homozygotes). https://gnomad.broadinstitute.org/variant/16-1637962-C-T The NM_014714.4(IFT140):c.1380del (p.Asn460fs) variant is present in gnomAD at a frequency of 0.000008804 in the European non-Finnish population (1/113590, with no homozygotes). https://gnomad.broadinstitute.org/variant/16-1633366-CG-C
VariantEvidence: NM_014714.4(IFT140):c.874G>A (p.Val292Met) is a missense variant that does not have functional evidence of gene impact. NM_014714.4(IFT140):c.1380del (p.Asn460fs) is a frameshift variant that introduces a premature stop codon in exon 12/31 and is predicted to trigger NMD or at least to truncate ~69% of the protein product.
CaseAddInfo: The proband's parents are each heterozygous for one variant.
CasePMIDs: N/A
Impacts of two point mutations of RPE65 from Leber's congenital amaurosis on the stability, subcellular localization and isomerohydrolase activity of RPE65
PMID: 16828753
Gene: RPE65
HGNC: 10294
Disease: Retinitis pigmentosa 20
MONDO: 0013425
InheritancePattern: Autosomal Recessive
Prevalence: The overall prevalence of Retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of recessive Retinitis pigmentosa caused by RPE65 variants is ~2%. (PMID: 9501220) Thus, the prevalence of Retinitis pigmentosa 20 is between 1 in 150,000 and 1 in 200,000.
Penetrance: Fully penetrant, with onset typically in childhood
Introduction
FamilyName: Selmer_Family
FamilyPresentingHPOFreeText: autosomal dominant pericentral retinal dystrophy (adPRD). Sixteen individuals (aged 23–78 years) were ophthalmologically examined as part of this project and 10 of them were assigned a diagnosis of PRD (Table 1). The ophthalmological examinations revealed an atypical form of retinitis pigmentosa (RP), which we prefer to call adPRD. Compared with classical RP, this phenotype has a favourable prognosis
CountryOrigin: Norway
FamilyPreviousTesting: We performed a genome-wide linkage analysis followed by sequencing of a candidate gene to identify the mutation causing the disease.
FamilyMethod1:
FamilyMethod2:
FamilyGenotypingMethod: Mutations in the RHO, RP1, RDS and IMPDH1 genes as a cause of adRP in this family were excluded in a separate study published elsewhere (Grøndahl et al. 2007). Genotyping was performed using the Affymetrix GeneChip® Human Mapping 10 K 2.0 array (Matsuzaki et al. 2004), according to the supplier’s protocol. All three exons of the TOPORS gene, including exon–intron boundaries, were sequenced.
Affected:
Unaffected:
Segregations:
PublishedLOD: 7.3
AddSegregationInfo: Preliminary results of linkage analysis showed a linkage peak with a LOD (logarithm of the odds) score of 2.6 covering the recently reported adRP gene TOPORS. This gene was sequenced in 19 family members and a missense mutation c.1205a>c was identified in exon 3 in all affected members, leading to a p.Q402P amino acid substitution. The mutation showed complete co-segregation with the disease (Fig. 1) in all members tested, and linkage analysis yielded a LOD score of 7.3, assuming complete penetrance and a mutation frequency of 0.001.
ProbandLabel: Selmer_Proband
Variant:
gnomAD: absent in gnomAD
CAID: CA373170940
Analysis of the OA1 gene reveals mutations in only one-third of patients with X-linked ocular albinism
PMID: 8634705
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.
Methods
Case: Patient 1
CasePresentingHPOsFreeText: A diagnosis of CSNB1 or CSNB2 was based on standard ERGs. The photopic ERG was the most specific criterion to distinguish between CSNB1 and CSNB2 because it showed a “square-wave” appearance in CSNB1 and a decreased b-wave in CSNB2. Patients with CSNB2 had rod- and cone-related problems. reduced visual acuity, nystagmus, symptoms of night blindness, or high refractive error at a young age.
CasePreviousTesting:
CaseGenotypingMethod: Molecular analysis was performed by direct Sanger sequencing of the entire coding regions in CACNA1F and CABP4 in patients with CSNB2. The coding exons and flanking intron sequences of the different CSNB2 genes were amplified by standardized polymerase chain reaction.
Variant: c.1075G>A (p.Gly359Arg)
ClinVarID: or CAID: CA412919833
gnomAD: variant not present in gnomAD v2.1.1
AddCaseInfo:
PreviouslyPublished:
VariantEvidence:
i
Case#: Haider_2000_Proband_6, sex, age, and origin not reported
CasePresentingHPOs: N/A
CaseHPOFreeText: The proband is part of a cohort in which all patients had a diagnosis of enhanced S-cone syndrome, based on electroretinogram and/or psychophysics, as well as optical coherence tomography. Other phenotypes within the cohort members (but not tracked individually) included increased sensitivity to blue light; visual loss, night blindness occurring from early in life, varying degrees of L-cone and M-cone vision, and retinal degeneration.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous genotyping was limited to Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.
CaseMethod1: Sanger sequencing of NR2E3
CaseMethod2: SSCP analysis of PCR products from NR2E3
CaseGenotypingMethod: Genotyping was performed by Sanger sequencing of NR2E3, followed by SSCP to screen other family members for the variant.
Variant: The individual harbors the NM_014249.4(NR2E3):c.310C>T (p.Arg104Trp) variant in the homozygous state.
ClinVarID: 846973
gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.00002739 (2 alleles / 73,032 total alleles) in the African / African-American population, with no homozygous occurrences. https://gnomad.broadinstitute.org/variant/chr15-71811830-C-T?dataset=gnomad_r4
VariantEvidence: NM_014249.4(NR2E3):c.310C>T (p.Arg104Trp) is a missense variant within the zinc finger / DNA-binding domain of NR2E3,.
CaseAddInfo: It is not clear whether or not the proband comes from a consanguineous family.
CasePMIDs: N/A
Our results revealed that the PRPF31 deficiency causes mis-splicing of genes involved in RNA processing (PRPF3, PRPF8, PRPF4, and PRPF19) and phototransduction (RHO, ROM1, FSCN2, GNAT2, and GNAT1) in the retina in the PRPF31 reduced samples. Mis-splicing of genes implicated in phototransduction was associated with photoreceptor degeneration observed in RP patients.
PRPF4, PRPF3, PRPF31, and PRPF8 are all splicing factors involved in mRNA processing and are encoded by genes that harbor variants associated with retinitis pigmentosa.
non-syndromic
Case#: Jespersgaard_2019_Patient_163, 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.612del (p.Lys205fs) variant in the homozygous state.
ClinVar: 636056
gnomAD: The NM_000440.3(PDE6A):c.612del (p.Lys205fs) variant is not found in gnomAD v2.1.1.
VariantEvidence: NM_000440.3(PDE6A):c.612del (p.Lys205fs) is a frameshift variant in exon 2 that is predicted to result in nonsense-mediated decay or at least to truncate the C-terminal ~76% of the protein product.
CaseAddInfo: N/A
CasePMIDs: N/A
To express the human CORD6 cyclase mutation in mouse rods, cDNA coding for the R838S RetGC1 was transferred from the expression vector used in HEK293 cells (Fig. 1) and inserted under the control of rod opsin promoter (47.Lem J. Applebury M.L. Falk J.D. Flannery J.G. Simon M.I. Tissue-specific and developmental regulation of rod opsin chimeric genes in transgenic mice.Neuron. 1991; 6: 201-210Abstract Full Text PDF PubMed Scopus (155) Google Scholar) in the transgene construct (Fig. 2A) injected in mouse eggs (see “Experimental Procedures” for details). Although CORD6 affects both rods and cones, we chose the promoter that is efficient only in rods to keep the non-expressing cones as a negative control group of photoreceptors in the same transgenic retinas and thus verify that any physiological changes we may observe specifically originate from the transgene-targeted photoreceptors. Founders screened for the presence of the transgenic construct (Fig. 2A) and passing the transgene to the progeny were then bred to wild type C67B6J mice for at least 4 consecutive generations to establish the R838S RetGC1 expressing lines (R838S+) 379 and 362 for subsequent detailed analysis. As will be demonstrated further in this article, the line 379 developed more gradually deterioration (arbitrarily dubbed “slower” line) and the line 362, a more severe phenotype (“faster” line).
ExperimentName: Transgenic mouse expressing human GUCY2D R838S
NonHumanModel: Mus musculus
GeneAlteration: A human GUCY2D transgene encoding the R838S substitution was placed under the control of the rod opsin promoter and injected into mouse eggs, creating a mouse model with rod-specific expression of the variant (and only inefficient expression in cones).
ModelPhenotype: HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0030483 (Reduced amplitude of dark-adapted bright flash electroretinogram a-wave), HP:0030478 (Abnormal amplitude of dark-adapted bright flash electroretinogram), HP:0030609 (Photoreceptor layer loss on macular OCT), HP:0410280 (Pediatric onset), HP:0000546 (Retinal degeneration)
HumanPhenotype: HP:0000548 (Cone/cone-rod dystrophy), HP:0007663 (Reduced visual acuity), HP:0007994 (Peripheral visual field loss), HP:0000613 (Photophobia), HP:0011504 (Bull's eye maculopathy), HP:0030465 (Undetectable light-adapted electroretinogram), HP:0030469 (Abnormal dark-adapted electroretinogram)
ModelEvidence: The model system approximately recapitulates the mode of inheritance (autosomal dominant) of the human disease state. At the molecular level, it increases the sensitivity of cGMP synthesis to calcium ion concentration (Figures 2B, 7A). At the ocular level, rod response (dark-adapted ERG) amplitudes were diminished starting at one month of age (Figure 4A, 4B), particularly by 6 months (Figure 5A, 5B), while cones lacking transgene expression remained functional (Figure 5A, 5C). Retinal morphology between 3 and 5 months of age showed outer nuclear layer reduction (Figures 6A, 7C) linked to photoreceptor loss (Figures 6B, 7D).
ModelVariant: NM_000180.4(GUCY2D):c.2512C>A (p.Arg838Ser) (ClinVar: 98568)
recessive mutations
FamilyLabel: van_Huet_2014_Family_F, family national origin reported as from Pakistan
Family#PresentingHPOs: HP:0410280 (Pediatric onset), HP:0000662 (Nyctalopia), HP:0000545 (Myopia), HP:0007663 (Reduced visual acuity), HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007737 (Bone spicule pigmentation of the retina)
FamilyHPOFreeText: The patient and family members have been diagnosed with retinitis pigmentosa, with macular abnormalities present in all cases.
Family#PresentingNotHPOs: N/A
CountryOrigin: Pakistan
Ethnicity: Not mentioned
Race: Not mentioned
Family#PreviousTesting: Previous genotyping outside of the IMPG2 locus has not been described for this family.
Family#Method1: Sanger sequencing of the 19 exons of the IMPG2 gene
Family#Method2: N/A
Family#GenotypingMethod: Genotyping may have been limited to Sanger sequencing of the 19 exons of the IMPG2 gene, as previous genotyping of other loci has not been described for this family.
Affected: 3
Unaffected: 3
Segregations: Two segregations are reported in the family, with none inconsistent. The family is apparently consanguineous, with the parents being first cousins. The pedigree is shown in Figure 1.
PublishedLOD: N/A
eLOD: 1.50
AddSegregationInfo: N/A
ProbandLabel: van_Huet_2014_Patient_F-II:2
Variant: The affected family members harbor the NM_016247.4(IMPG2):c.1680T>A (p.Tyr560Ter) variant in the homozygous state.
ClinVar: 437938
gnomAD: This variant was not found in gnomAD v2.1.1.
FamilyAddInfo: The family is reportedly consanguineous, with the parents being first cousins.
FamilyPMIDs: N/A
A novel Ser156Cys mutation in the tissue inhibitor of metalloproteinases-3 (TIMP3) in Sorsby's fundus dystrophy with unusual clinical features
PMID: 8634721
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
The whole-genome sequence contained a homozygous nonsense mutation: CLN5:c.619C>T. All 4 DNA samples from clinically affected dogs tested homozygous for the variant allele. Both parents of the fifth affected dog were heterozygotes.
ExperimentName: Genotyping of 4 Australian Cattle Dogs affected with NCL
NonHumanModel: Canis familiaris
GeneAlteration: While the model does not have an engineered gene alteration, all four affected animals are homozygous for the CLN5:c.619C>T variant. The unaffected parents of a fifth affected dog were both heterozygotes for this variant.
ModelPhenotype: HP:0001250 (Seizure), HP:0000572 (Visual loss), HP:0000708 (Behavioral abnormality), HP:0002370 (Poor coordination), HP:0002312 (Clumsiness), HP:0001251 (Ataxia), HP:0100299 (Muscle fiber inclusion bodies), HP:0002283 (Global brain atrophy), HP:0002119 (Ventriculomegaly), Note: inclusion bodies are membrane-associated and autofluorescent. Onset of phenotypes was between 12-18 months, and the condition was rapidly progressive, with euthanasia occurring between 20-27 months of age.
HumanPhenotype: 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:0100952 (Enlarged sylvian cistern), HP:0002059 (Cerebral atrophy), HP:0001272 (Cerebellar atrophy)
ModelEvidence: The model phenotypes closely match the human patient phenotypes in the timing of onset and rapid progression (Table 3), neurological details, vision problems, loss of coordination, and microscopic accumulation of storage/inclusion bodies (Figure 4, Figure 5).
ModelVariant: CLN5:c.619C>T p.Gln207Ter
4
Case#: Xin_Patient_8, sex not mentioned, age 5.5 at onset, U.S. nationality, Indian ethnicity
CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000512 (Abnormal electroretinogram), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0011463 (Childhood onset)
CaseHPOFreeText: Motor difficulty was the phenotype at presentation (age 5.5). Cognitive regression (age 6), and visual findings (abnormal ERG) had later onset.
CaseNotHPOs: HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material)
CaseNotHPOFreeText: The electron microscopy findings referred to above (from conjunctiva biopsy) were normal.
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.428A>G p.Asn143Ser variant.
ClinVar: 56539 (homozygous)
gnomAD: The NM_006493.4(CLN5):c.428A>G p.Asn143Ser variant is absent from gnomAD.
VariantEvidence: NM_006493.4(CLN5):c.428A>G p.Asn143Ser is a missense variant at a highly conserved residue, and is speculated by the authors to function as an exonic splicing enhancer. SpliceAI finds some evidence of a possible donor loss (change score of 0.02) or acceptor gain (change score of 0.09).
CaseAddInfo: Parents have not been subjected to genotyping, so homozygosity of variants is assumed. This conclusion was supported by failure to detect a deletion. Family history of non-consanguinity or consanguinity was not mentioned, but both parents share the same local area of origin within India.
CasePMIDs: N/A
Identification of GUCY2D gene mutations in CORD5 families and evidence of incomplete penetrance
PMID: 12552567
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.
We generated D477G RPE65 KI mice by replacing the endogenous RPE65 gene with a targeting vector including exons 8–14 along with the D477G mutation (Fig. 2A). A neomycin (Neo) cassette flanked by Flp-recombinase target (FRT) sites was used for clonal selection and later excised by FLP recombinase expressed in the embryonic stem cells. The embryonic stem cells carrying the Neo deleted targeting vector were microinjected into C57Bl/6 blastocysts.
ExperimentName: Recombinase-based variant knock-in to the mouse Rpe65 locus
NonHumanModel: Mus musculus
GeneAlteration: A substitution equivalent to the human NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant was knocked into the mouse Rpe65 locus by Flp-recombinase, which allowed the selection cassette to be subsequently excised.
ModelPhenotype: HP:0030602 (Abnormal fundus autofluorescence imaging), HP:0030329 (Retinal thinning), HP:0030483 (Reduced amplitude of dark-adapted bright flash electroretinogram a-wave), HP:0008275 (Abnormal light-adapted electroretinogram)
HumanPhenotype: HP:0000662 (Nyctalopia), HP:0007688 (Undetectable light- and dark-adapted electroretinogram), HP:0001098 (Abnormal fundus morphology), HP:0000529 (Progressive visual loss)
ModelEvidence: The mice exhibit reduced levels of RPE65 protein (Figure 3A) and enhanced ubiquitination (Figure 3B), indicating higher susceptibility to proteolysis. Despite normal 11-cis retinal levels (Figure 7C), the heterozygous knock-in animals exhibit abnormal accumulation of retinyl esters (Figure 7B), recapitulating a key molecular defect of the human patients. Photobleaching revealed defects in regeneration of 11-cis-retinal (Figure 7F) and accumulation of retinyl esters (Figure 7G). These defects were observable in both the heterozygous knock-in (mild) and homozygous knock-in (more severe). Accumulation of autofluorescent spots in the fundus (Figure 4), progressive thinning of the outer nuclear layer (Figure 5), and abnormal ERG responses (Figure 6) were seen in heterozygous knock-in and especially homozygous knock-in mice with age. Similar phenotypic results were observed with a third, similar knock-in mouse model (PMID: 28041994).
ModelVariant: The model knocks the NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant (ClinVar:750796) into the endogenous mouse Rpe65 locus.