004–2013
Case#: 004-2013
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.6046C>T
LegacyVariant:
ClinVar: No
CAID: CA255197
gnomAD:
022–2007
Case#: 022-2007
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.73_75delTAC
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
015–2008
Case#: 015-2008
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.dupexons7_22
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
001–2052
Case#: 001-2052
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.1988C>T
LegacyVariant:
ClinVar: No
CAID: CA255135
gnomAD:
050–1001
Case#: 050-1001
DiseaseAssertion: Hemophilia A, moderate
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.6046C>T
LegacyVariant:
ClinVar: No
CAID: CA255197
gnomAD:
003–1002
Case#: 003-1002
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: NM_000132.3:c.493C>T
LegacyVariant:
ClinVar: No
CAID: CA255065
gnomAD:
001–2022
Case#: 001-2022
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.947_949insA
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
060–2008
Case#: 060-2008
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1618C>A
LegacyVariant:
ClinVar: No
CAID: CA414911950
gnomAD:
047–1007
Case#: 047-1007
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.1093T>G
LegacyVariant:
ClinVar: No
CAID: CA414916885
gnomAD:
020–2015
Case#: 020-2015
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.5612T>G
LegacyVariant:
ClinVar: No
CAID: CA414908197
gnomAD:
028–1001
Case#: 028-1001
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant:
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
004–2025
Case#: 004-2025
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.328A>G
LegacyVariant:
ClinVar: No
CAID: CA255057
gnomAD:
001–2049
Case#: 001-2049
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:
004–2007
Case#: 004-2007
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.3637delA
LegacyVariant:
ClinVar: No
CAID: CA255146
gnomAD:
045–2002
Case#: 045-2002
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 1% < FVIII:C < 5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.3637delA
LegacyVariant:
ClinVar: No
CAID: CA255146
gnomAD:
003–2012
Case#: 003-2012
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.992T>C
LegacyVariant:
ClinVar: No
CAID: CA414917621
gnomAD:
003–2017
Case#: 003-2017
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.4379dupA
LegacyVariant:
ClinVar: No
CAID: CA645292749
gnomAD:
020–2052
Case#: 020-2052
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.923C>T
LegacyVariant:
ClinVar: No
CAID: CA255082
gnomAD:
003–2007
Case#: 003-2007
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.1475A>G
LegacyVariant:
ClinVar: No
CAID: CA337334224
gnomAD:
047–1001
Case#: 047-1001
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant:
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
087–2003
Case#: 087-2003
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.5122C>T
LegacyVariant:
ClinVar: No
CAID: CA120919
gnomAD:
038–2016
Case#: 038-2016
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.3531_3533delA
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
020–2045
Case#: 020-2045
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.458A>T
LegacyVariant:
ClinVar: No
CAID: CA414919676
gnomAD:
038–1003
Case#: 038-1003
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.331G>A
LegacyVariant:
ClinVar: No
CAID: CA414919991
gnomAD:
035–1003
Case#: 035-1003
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:
084–2006
Case#: 084-2006
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1910A>G
LegacyVariant:
ClinVar: No
CAID: CA414909849
gnomAD:
001–2045
Case#: 001-2045
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.1462G>A
LegacyVariant:
ClinVar: No
CAID: CA414912862
gnomAD:
071–2032
Case#: 071-2032
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.308_319delGTGGTCATTACA
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
001–2028
Case#: 001-2028
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.4379dupA
LegacyVariant:
ClinVar: No
CAID: CA645292749
gnomAD:
038–2020
Case#: 038-2020
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.3637delA
LegacyVariant:
ClinVar: No
CAID: CA255146
gnomAD:
035–2017
Case#: 035-2017
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1834C>T
LegacyVariant:
ClinVar: No
CAID: CA255129
gnomAD:
156
Case#: 156, male, 23 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.3637delA
LegacyVariant:
ClinVar: No
CAID: CA255146
gnomAD:
121
Case#: 121, male, 16 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 2%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.5586+2T>A
LegacyVariant:
ClinVar: No
CAID: CA414908347
gnomAD:
131
Case#: 131, male, 23 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: na
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 1.5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.4379dupA
LegacyVariant:
ClinVar: No
CAID: CA645292749
gnomAD:
126
Case#: 126, male, 33 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 7.9%
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.2133_2134insT
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
48
Case#: 48, male, 37 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 1.2%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.1331A>C
LegacyVariant:
ClinVar: No
CAID: CA414914983
gnomAD:
38
Case#: 38, male, 10 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 13%
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.530A>G
LegacyVariant:
ClinVar: No
CAID: CA414919515
gnomAD:
59
Case#: 59, male, 13 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 1.1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.1913G>A
LegacyVariant:
ClinVar: No
CAID: CA414909831
gnomAD:
57
Case#: 57, male, 9 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.1909A>G
LegacyVariant:
ClinVar: No
CAID: CA414909856
gnomAD:
119
Case#: 119, male, 10 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 3.3%
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.5219+3A>G
LegacyVariant:
ClinVar: No
CAID: CA873340051
gnomAD:
35
Case#: 35, male, 19 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.385G>C
LegacyVariant:
ClinVar: No
CAID: CA414919872
gnomAD:
155
Case#: 155, male, 27 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 1.4%
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:
28
Case#: 28, male, 55 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.301G>C
LegacyVariant:
ClinVar: No
CAID: CA414920057
gnomAD:
51
Case#: 51, male, 8 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 22%
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.1758G>A
LegacyVariant:
ClinVar: No
CAID: CA414911269
gnomAD:
67
Case#: 67, male, 30 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.2167G>A
LegacyVariant:
ClinVar: 10246
CAID: CA255138
gnomAD:
169
Case#: 169, male, 25 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.6254delA
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
78
Case#: 78, male, 44 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 21%
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.5558C>T
LegacyVariant:
ClinVar: 10284
CAID: CA255174
gnomAD:
149
Case#: 149, male, 37 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 2.1%
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.1780delC
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
116
Case#: 116, male, 29 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.1443+2T>G
LegacyVariant:
ClinVar: No
CAID: CA414914230
gnomAD:
173
Case#: 173, male, 21 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.del exons1_26
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
86
Case#: 86, male, 63 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 26%
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.6380A>G
LegacyVariant:
ClinVar: No
CAID: CA414899587
gnomAD:
135
Case#: 135, male, 54 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.5961dupA
LegacyVariant:
ClinVar: No
CAID: CA645251974
gnomAD:
82
Case#: 82, male, 38 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.5720G>A
LegacyVariant:
ClinVar: No
CAID: CA414907651
gnomAD:
55
Case#: 55, male, 36 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 17%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.1834C>T
LegacyVariant:
ClinVar: 10236
CAID: CA255129
gnomAD:
18
Case#: 18, male, 15 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 20%
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.3325C>T
LegacyVariant:
ClinVar: No
CAID: CA414897253
gnomAD:
144
Case#: 144, male, 14 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 1.1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.4320_4325delTAGAAA
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
160
Case#: 160, 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.3637delA
LegacyVariant:
ClinVar: No
CAID: CA255146
gnomAD:
185
Case#: 185, male, 29 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.del exon26
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
110
Case#: 110, male, 9 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.7021G>C
LegacyVariant:
ClinVar: No
CAID: CA414896760
gnomAD:
130
Case#: 130, male, 16 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 17.5%
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.3802dupC
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
50
Case#: 50, male, 50 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 16.3%
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.1745G>A
LegacyVariant:
ClinVar: No
CAID: CA414911614
gnomAD:
95
Case#: 95, male, 76 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 17%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6506G>A
LegacyVariant:
ClinVar: 10315
CAID: CA255208
gnomAD:
33
Case#: 33, male, 25 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 3.8%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.382T>C
LegacyVariant:
ClinVar: 811825
CAID: CA414919878
gnomAD:
103
Case#: 103, male, 10 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.6635C>T
LegacyVariant:
ClinVar: No
CAID: CA414905841
gnomAD:
113
Case#: 113, male, 27 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.388+5G>A
LegacyVariant:
ClinVar: No
CAID: CA873357439
gnomAD:
22
Case#: 22, male, 30 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 3.1%
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.6496C>T
LegacyVariant:
ClinVar: 10096
CAID: CA255013
gnomAD:
72
Case#: 72, male, 31 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 4.6%
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.5399G>A
LegacyVariant:
ClinVar: 10274
CAID: CA255162
gnomAD:
44
Case#: 44, male, 9 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 1.7%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.1171C>T
LegacyVariant:
ClinVar: 10125
CAID: CA255026
gnomAD:
A14 A15
Case#: A14, A15
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 15, FVIII:AG = 41, 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.5530C>T
LegacyVariant:
ClinVar: No
CAID: CA255170
gnomAD:
B79 – B82
Case#: B79 - B82
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C Chr = 7, FVIII:AG = 15, 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.6413C>A
LegacyVariant:
ClinVar: No
CAID: CA255204
gnomAD:
B28. B29
Case#: B28, B29
DiseaseAssertion: NA
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C Chr = 78, FVIII:AG = 94, 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.2089G>C
LegacyVariant:
ClinVar: No
CAID: CA414909014
gnomAD:
A4
Case#: A4
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 6, FVIII:AG = 15, 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.896A>T
LegacyVariant:
ClinVar: No
CAID: CA255078
gnomAD:
c.5953C>T
Case#: 23
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C <1% (Severe Phenotype), No inhibitors present
CasePreviousTesting: Screened for IVS-22 and IVS-1, Possibility that sample was blinded for NGS and validated by comparing results with Sanger Sequencing
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.6977G>A
Case#: 37
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 36%, 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.6977G>A (p.Arg2326Gln)
ClinVar: 10126 https://www.ncbi.nlm.nih.gov/clinvar/variation/10126/
CAID: CA255027
gnomAD: Not reported
c.197A>T
Case#: 1
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 21% (Mild Phenotype), No inhibitors present
CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing
Gene: F8
Variant: NM_000132.3:c.197A>T (p.Lys66Ile)
ClinVar: NA
CAID: CA414920295
gnomAD: Not reported
c.5213delG
Case#: 21
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C <=1% (Severe Phenotype), No inhibitors present
CasePreviousTesting: Screened for IVS-22 and IVS-1, Possibility that sample was blinded for NGS and validated by comparing results with Sanger Sequencing
Gene: F8
Variant: NM_000132.3:c.5213del
ClinVar: NA
CAID: CA1139532038
gnomAD: Not reported
c.835G>A
Case#: 47
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C 18/26% (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_000133.3(F9):c.835G>A (p.Ala279Thr)
ClinVar: 216926 https://www.ncbi.nlm.nih.gov/clinvar/variation/216926/
CAID: CA277507
gnomAD: Not reported
c.541G>A
Case#: 4
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 3/5/3% (Moderate Phenotype), No inhibitors present
CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing
Gene: F8
Variant: NM_000132.3(F8):c.541G>A (p.Val181Met)
ClinVar: 10177 https://www.ncbi.nlm.nih.gov/clinvar/variation/10177/
CAID: CA255066
gnomAD: Not reported
c.5374–19delT
Case#: 22, Female HA carrier
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 60%, 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.5374-19del
ClinVar: 439679 https://www.ncbi.nlm.nih.gov/clinvar/variation/439679/
CAID: CA10567985
gnomAD: MAF in the South Asian population 0.3867<br>https://gnomad.broadinstitute.org/variant/X-154133316-CA-C
c.4692delC
Case#: 19
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C <1% (Severe Phenotype), No inhibitors present
CasePreviousTesting: Screened for IVS-22 and IVS-1, Possibility that sample was blinded for NGS and validated by comparing results with Sanger Sequencing
Gene: F8
Variant: NM_000132.3:c.4692del (p.Leu1566Ter)
ClinVar: NA
CAID: CA1139532037
gnomAD: NA
Table 2
Case#: Cz39, 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
Screening of mutations of hemophilia A in 40 Italian patients: a novel G-to-A mutation in intron 10 of the F8 gene as a putative cause of mild hemophilia a in southern Italy
PMID: 18388498
Gene: F8
HGNCID: 3546
Table 2
Case#: Cz15, Italy (Calabria)
DiseaseAssertion: Hemophilia A
FamilyInfo: Inherited
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVII:C 2.4%
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#: Cz8, 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#: Cz17, Italy (Calabria)
DiseaseAssertion: Hemophilia A
FamilyInfo: Inherited
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVII:C <1%
CasePreviousTesting: Polymerase chain reaction (PCR) analysis, Long PCR for detecting the intron 22 inversion was performed, Direct cycle sequence analysis using the Taq dye-deoxy terminator method
Gene: F8
Variant: NM_000132.3:c.3224del (p.Ala1075ValfsTer4)
ClinVar: NA
CAID: NA
gnomAD: Not reported
Table 2
Case#: Cz4, Italy (Calabria)
DiseaseAssertion: Hemophilia A
FamilyInfo: Inherited
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVII:C 2.4%
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#: Cz38, 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 2
Case#: Cz10, 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#: Cz16, 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
Table 2
Case#: Cz27, Italy (Calabria)
DiseaseAssertion: Hemophilia A
FamilyInfo: Inherited
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVII:C 3.5%
CasePreviousTesting: Polymerase chain reaction (PCR) analysis, Long PCR for detecting the intron 22 inversion was performed, Direct cycle sequence analysis using the Taq dye-deoxy terminator method
Gene: F8
Variant: NM_000132.3:c.1538-18G>A
ClinVar: 811357 https://www.ncbi.nlm.nih.gov/clinvar/variation/811357/
CAID: CA873354114
gnomAD: Not reported
S25
Case#: S25, Iranian
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Family history of HA
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.3870dupA
LegacyVariant:
ClinVar: No
CAID: CA645616770
gnomAD:
S7
Case#: S7, 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.1444‐1G>T
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
S4
Case#: S4, 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: NA
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
S11
Case#: S11, 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:
S14
Case#: S14, 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.575T>C
LegacyVariant:
ClinVar: No
CAID: CA414919417
gnomAD:
Risk factors for inhibitor development in severe hemophilia A
PMID: 29879570
Gene: F8
HGNC: 3546
InsufficientEvidence: This article is a review, so no new case reports have been mentioned here
PreviouslyPublished
A novel missense mutation in F9 gene causes hemophilia B in a family with clinical variability
PMID:
Gene: F9
HGNCID: 3551
3-year-old boy
Case1: 3-year-old boy
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: The pathogenic mutation of F9 gene in this family was identified, Mother and Grandmother are HB carriers, Father tested negative. Pedigree shown in Figure 1.
ParentalTesting: Sequences at the mutation locus in F9 genes were analyzed by Sanger sequencing.
CasePresentingHPOs: NA
CaseHPOFreeText: Hemorrhagic spots on his skin at birth, Gingival bleeding, APTT 66.5 s, FIX:C < 1%, FVIII:C 116.8%
CasePreviousTesting: PCR amplification for coding and flanking sequences of F9 gene, PCR amplification products sequenced by Songon Biotech Co. Ltd.
Gene: F9
Variant: NM_000133.3:c.1232G>C (p.Ser411Thr)
ClinVar: NA
CAID: CA414446686
gnomAD: NA
Genetic analysis of a hemophilia B family with a novel F9 gene mutation
PMID: 31124946
Gene: F9
HGNCID: 3551
UQU-HB3
Case#: UQU-HB3, Male, 1-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe, PTT 50.9, Disabled left ankle
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-HB9
Case#: UQU-HB9, Male, 1-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Moderate, PTT 51.4, Unable to flex knees fully
CasePreviousTesting: Screened for all factor IX exons by capillary sequencing
Gene: F9
Variant: NM_001313913.1:c.580G>A
ClinVar: NA
CAID: CA414441211
gnomAD: Not reported
UQU-HB11
Case#: UQU-HB11, Male, 1-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0001892 (Abnormal bleeding)
CaseHPOFreeText: Severe, Unable to flex elbows fully, PTT 148.3
CasePreviousTesting: Screened for all factor IX exons by capillary sequencing
Gene: F9
Variant: NM_000133.4(F9):c.855G>C (p.Glu285Asp)
ClinVar: 828138 https://www.ncbi.nlm.nih.gov/clinvar/variation/828138/
CAID: CA414444506
gnomAD: Not reported
C.6427A>G
Case#: 28
DiseaseAssertion: Hemophilia A
FamilyInfo: Sporadic
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Mild
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.6427A>G (p.Met2124Val)
ClinVar: NA
CAID: CA414899297
gnomAD: Not reported
c.1910A>T
Case#: 23
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.1910A>T (p.Asn618Ile)
ClinVar: NA
CAID: CA414909847
gnomAD: Not reported
c.1180G>T
Case#: 18, Spanish
DiseaseAssertion: Hemophilia A
FamilyInfo: Positive
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Mild
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.1180G>T (p.Ala375Ser)
ClinVar: NA
CAID: CA414916327
gnomAD: Not reported
c.5805T>A
Case#: 8
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.5805T>A (p.Tyr1935Ter)
ClinVar: NA
CAID: CA414906924
gnomAD: Not Reported
c.1251insC
Case#: 1
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.1251_1252insC (p.Val418ArgfsTer6)
ClinVar: NA
CAID: CA1139532040
gnomAD: Not reported
A Novel Missense Mutation, E1623G, in the Human Factor VIII Gene Associated With Moderate Haemophilia A
PMID: 24719712
Gene: F8
HGNCID: 3546
In the index patient (IV1) of family OA1-3 that did not show exon deletion, sequence analysis of all coding exons including the exon-intron boundaries revealed a deletion of a single nucleotide G at position 310 of the cDNA introducing a subsequent premature stop codon one codon downstream, predicting a deleterious protein product. This newly described mutation (310delG) in exon 2 of the OA1 gene creates a TaqI restriction site. Although the pedigree of family OAI-3 initially suggested the patient IV1 to be a sporadic case, PCR-restriction analysis identified the patient's maternal uncle (III3), known to have only a decreased visual acuity at age 38, as hemizygous for the mutation. The mother (III2) and the maternal grand-mother (II1) of the proband were found to be carriers (Fig. (Fig.4B),4B), as expected
Case#: Faugere_2003_Family_OA1-3_Patient_IV1, male, 26 years of age at time of report, family origin reported to be from the South of France with race described as Caucasian
CasePresentingHPOs: HP:0006934 (Congenital nystagmus), HP:0007750 (Hypoplasia of the fovea), HP:0007663 (Reduced visual acuity), HP:0001089 (Iris atrophy), HP:0012805 (Iris transillumination defect), HP:0007894 (Hypopigmentation of the fundus), HP:0030602 (Abnormal fundus autofluorescence imaging), HP:0030479 (Abnormal amplitude of light-adapted flicker electroretinogram)
CaseHPOFreeText: The proband was initially diagnosed with congenital nystagmus.
CaseNotHPOs: HP:0012632 (Abnormal intraocular pressure), HP:0000518 (Cataract)
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous testing was not described, however, the proband was examined for whole-exon deletions using PCR amplification of the 9 exons from the GPR143 locus.
CaseMethod1: Sanger sequencing
CaseMethod2: Restriction enzyme analysis using TaqI
CaseGenotypingMethod: The proband was examined for whole-exon deletions using PCR amplification of the 9 exons from the GPR143 locus, followed by Sanger-based sequencing and restriction enzyme-based screening of family members using TaqI.
Variant: The proband harbors the NM_000273.3(GPR143):c.310del (p.Asp104fs) variant in the hemizygous state.
ClinVar: 98625
gnomAD: This variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_000273.3(GPR143):c.310del (p.Asp104fs) is a frameshift variant in exon 2 of 9, and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 75% of the protein product.
CaseAddInfo: While the proband was initially thought to be a sporadic case, the variant was later found to be maternally inherited, with an uncle found to harbor the variant and to be affected with decreased visual acuity. Further details of the family member are not described.
CasePMIDs: N/A
Atypical sorsby fundus dystrophy with a novel tyr159cys timp-3 mutation
PMID: 25390527
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
(f) Presynaptic localization of mouse CaBP4 (red) demonstrated by covisualization with a presynaptic protein (PSD95; green). Arrows indicate rod spherules and cone pedicles. (g) Colocalization of synaptic vesicle proteins SV2 and synaptophysin (green) with mouse CaBP4 (red).
Biochemical evidence showing mouse CaBP4 (red) localization to the presynaptic region based on co-localization with the PSD95 marker (green).
A nonhuman primate model of inherited retinal disease
PMID: 30667376
A developmentally regulated microsomal protein specific for the pigment epithelium of the vertebrate retina
PMID: 8474143
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
Biochemical Basis for Dominant Inheritance, Variable Penetrance, and Maternal Effects in RBP4 Congenital Eye Disease
PMID: 25910211
A2014-II1
Case#: Harville_2010_Patient_A2014-II1, sex assumed to be male based on phenotypes, age not reported, family origin reportedly from Turkey
CasePresentingHPOs: HP:0010442 (Polydactyly), HP:0001513 (Obesity), HP:0000135 (Hypogonadism), HP:0000077 (Abnormality of the kidney)
CaseHPOFreeText: The proband has an initial clinical diagnosis of Bardet-Biedl syndrome. Secondary signs are noted as present, but specifics are not reported.
CaseNotHPOs: HP:0000510 (Rod-cone dystrophy)
CaseNotHPOFreeText: The proband reportedly does not have retinitis pigmentosa. Age has not been reported in the study.
CasePreviousTesting: The proband was initially subjected to homozygosity mapping to identify parts of the genome to search for the basis of recessive disease.
CaseMethod1: homozygosity mapping
CaseMethod2: Sanger sequencing of the exons of any of the 14 BBS-associated loci (BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, TRIM32, BBS12, MKS1, and CEP290) that showed homozygosity.
CaseGenotypingMethod: The proband was initially subjected to homozygosity mapping to identify parts of the genome to search for the basis of recessive disease. This was followed by Sanger sequencing of the exons of any of the 14 BBS-associated loci (BBS1, BBS2, ARL6, BBS4, BBS5, MKKS, BBS7, TTC8, BBS9, BBS10, TRIM32, BBS12, MKS1, and CEP290) that showed homozygosity.
Variant: The proband harbors the NM_024649.5(BBS1):c.48-1G>A variant in the homozygous state.
ClinVar ID: 1299580
gnomAD: The NM_024649.5(BBS1):c.48-1G>A variant is found in gnomAD v2.1.1 at a frequency of 0.000008790 in the European (non-Finnish) population, with 1 allele / 113768 total alleles (0 homozygotes) https://gnomad.broadinstitute.org/variant/11-66278483-G-A?dataset=gnomad_r2_1
VariantEvidence: NM_024649.5(BBS1):c.48-1G>A is a canonical splice site variant predicted but not confirmed to disrupt BBS1 splicing.
CaseAddInfo: The proband's family is reportedly consanguineous.
CasePMIDs: N/A
Mutations in LRP5 or FZD4 Underlie the Common Familial Exudative Vitreoretinopathy Locus on Chromosome 11q
PMID: 15024691
Gene: LRP5
HGNC: 6697
Disease: osteoporosis-pseudoglioma syndrome
MONDO: 0009820
InheritancePattern: autosomal recessive
Prevalence: osteoporosis-pseudoglioma syndrome is estimated to occur in 1 out of every 2,000,000 live births.
Penetrance: The penetrance of the phenotype among homozygous or compound heterozygous cases appears to be complete, while heterozygous carriers of deleterious variants appear to be mildly affected.
We show that, in the retina, CEP290 associates with several microtubule-based transport proteins including RPGR, which is mutated in ~15% of patients with retinitis pigmentosa.
ExperimentName: Co-IP showing interaction of RPGR with CEP290
InteractingGene: CEP290, which is implicated in Leber congenital amaurosis 10 and multiple syndromic phenotypes (Joubert syndrome, Meckel syndrome, and Senior-Loken syndrome).
InteractionType: Physical
InteractionMethod: Co-immunoprecipitation was performed with a positive result, while yeast-2-hybrid (Y2H) was performed with a negative result.
InteractionEvidence: Co-IP with an RPGR antibody (Figure 4A) or CEP290 antibody (Figure 4B) successfully immunoprecipitates both proteins from wild-type mouse retinal extracts. The two (endogenously expressed) proteins also co-localize in IMDC-3 cells (Figure 4C). However, yeast 2-hybrid experiments do not confirm this interaction as direct (data not shown).
Moreover, we show that the spontaneous mouse mutant cpfl1 that features a lack of cone function and rapid degeneration of the cone photoreceptors represents a homologous mouse model for PDE6C associated achromatopsia.
ExperimentName: The Cpfl1 mouse harbors loss-of-function variants in the Pde6c gene.
NonHumanModel: Mus musculus
GeneAlteration: The model animals are homozygous for two different loss-of-function variants predicted to introduce premature stop codons into the Pde6c locus. One is a 116-bp insertion between exons 4 and 5, while the other is a 1-bp deletion in exon 7.
ModelPhenotype: HP:0008020 (cone dystrophy), HP:0030465 (Undetectable light-adapted electroretinogram), normal dark-adapted ERG, rapid and progressive loss of cone photoreceptors from the photoreceptor layer
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 mouse model with lack of light-adapted ERG responses and normal dark-adapted ERG responses (Figure 1). The mice also exhibit rapid and progressive loss of cone photoreceptors from retinal sections (Figure 2).
ModelVariant: This model did not introduce a disease-associated variant known from an affected human patient, but rather studied naturally occurring variants disrupting the Pde6c locus.
We then extended our mutation screening study to include 24 additional simplex achromatopsia patients that were also prescreened and did not carry mutations in the known achromatopsia genes. Among those 24 patients, we identified one further subject (CHRO 287) with two heterozygous nonsense mutations, c.826C>T/p.Arg276X and c.2457T>A/p.Tyr819X
Case#: Chang_2009_Family_CHRO287_Proband_II:1, male, age and family origin not described
CasePresentingHPOs: HP:0011516 (Achromatopsia)
CaseHPOFreeText: The proband was previously diagnosed with achromatopsia.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: The proband and his parents were initially subjected to genotyping of the CNGA3, GNGB3, and GNAT2 loci, confirming absence of causal variants in these known achromatopsia-related genes.
CaseMethod1: Sanger sequencing of CNGA3, GNGB3, and GNAT2
CaseMethod2: Sanger sequencing of the 22 exons and flanking regions of PDE6C
CaseGenotypingMethod: CNGA3, GNGB3, and GNAT2 were previously screened / known not to harbor causal variants for achromatopsia. The family members were then subjected to Sanger sequencing of the 22 exons and flanking regions of PDE6C.
Variant: The proband harbors the NM_006204.4(PDE6C):c.826C>T (p.Arg276Ter) and NM_006204.4(PDE6C):c.2457T>A (p.Tyr819Ter) variants in the compound heterozygous state.
ClinVar ID: 8773, 8774
gnomAD: The NM_006204.4(PDE6C):c.826C>T (p.Arg276Ter) variant is found in gnomAD v2.1.1 at a frequency of 0.00006152 (1 allele / 16256 total alleles) in the African / African-American population, with 0 homozygotes. The NM_006204.4(PDE6C):c.2457T>A (p.Tyr819Ter) variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_006204.4(PDE6C):c.826C>T (p.Arg276Ter) is a nonsense variant in exon 4 of 22 and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 68% of the protein product. NM_006204.4(PDE6C):c.2457T>A (p.Tyr819Ter) is a nonsense variant in exon 21 of 22 and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 5% of the protein product.
CaseAddInfo: The patient has an affected brother who shares the same compound heterozygous genotype, while the parents and one other sibling are each unaffected carriers.
CasePMIDs: N/A
mutation
Case#: Mykykyn_2002_Proband_PR2-1, gender not specified, age not described, family origin reported as from Puerto Rico
CasePresentingHPOs: N/A
CaseHPOFreeText: The proband has been previously diagnosed with Bardet-Biedl syndrome based on at least three of the following features; obesity, polydactyly, renal anomalies, retinopathy, hypogonadism, and/or mental retardation.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: The proband and their affected and unaffected family members were subjected to mapping of the disease-associated locus to chromosome 11, followed by PCR- and Sanger sequencing-based genotyping of chromosome 11 markers.
CaseMethod1: linkage mapping
CaseMethod2: Sanger sequencing of BBS1
CaseGenotypingMethod: The proband and their affected and unaffected family members were subjected to linkage mapping of the disease-associated locus to chromosome 11, followed by PCR- and Sanger sequencing-based genotyping of chromosome 11 markers. Sanger sequencing of BBS1 was subsequently used to identify the variant.
Variant: The proband harbors the NM_024649.5(BBS1):c.1645G>T (p.Glu549Ter) variant in the homozygous state.
ClinVar ID: 12144
gnomAD: The variant is found in gnomAD v2.1.1 at a frequency of 0.00008675 (3 alleles out of 34584 total alleles, with 0 homozygotes) in the Admixed American population https://gnomad.broadinstitute.org/variant/11-66299163-G-T?dataset=gnomad_r2_1
VariantEvidence: NM_024649.5(BBS1):c.1645G>T (p.Glu549Ter) is a nonsense variant in exon 16 of 17 that is predicted to not to trigger nonsense-mediated decay but rather to truncate the C-terminal 8% of the protein product.
CaseAddInfo: The proband's family is described as consanguineous.
CasePMIDs: N/A
RBP3-Retinopathy-Inherited High Myopia and Retinal Dystrophy: Genetic Characterization, Natural History, and Deep Phenotyping
PMID: 37806543
Gene: RBP3
HGNC: 9921
Disease: retinitis pigmentosa 66
MONDO: 0014093
InheritancePattern: autosomal recessive
Prevalence: RBP3-related cases are believed to be very rare (possibly with estimated prevalence of less than 1 in 1,000,000), however, it is believed that there may be under-diagnosis (PMID: 37806543).
Penetrance: RBP3 disease-causing variants appear to have complete penetrance.
Photoreceptor-specific nuclear receptor NR2E3 functions as a transcriptional activator in rod photoreceptors
PMID: 15190009
Gene: NR2E3
HGNC: 7974
Disease: enhanced S-cone syndrome
MONDO: 0100288
InheritancePattern: autosomal recessive
Prevalence: The overall prevalence of enhanced S cone syndrome is <1 in 1,000,000 (PMID: 30900587).
Penetrance: The penetrance of enhanced S-cone syndrome has been difficult to determine accurately given the rarity of the condition.
Comprehensive Rare Variant Analysis via Whole-Genome Sequencing to Determine the Molecular Pathology of Inherited Retinal Disease
PMID: 28041643
Gene: IMPG2
HGNC: 18362
Disease: retinitis pigmentosa 56
MONDO: 0013314
InheritancePattern: semi-dominant
Prevalence: Vitelliform macular dystrophy in general is estimated to have a prevalence of 1 in 5,500 (PMID: 27120116).
Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete, while heterozygous carriers of deleterious variants show incomplete penetrance and variable expressivity.
TRPM1 is required for the depolarizing light response in retinal ON-bipolar cells
PMID: 19861548
Gene: TRPM1
HGNC: 7146
Disease: congenital stationary night blindness 1C
MONDO: MONDO:0013183
InheritancePattern: autosomal recessive
Prevalence: Congenital stationary night blindness has an estimated prevalence between 1 in 6,000 (PMID: 31427709) and 1 in 300,000 (PMID: 3487908). However, the prevalence of congenital stationary night blindness 1C specifically is unknown.
Penetrance: Penetrance is thought to be complete.
Osteoporosis-pseudoglioma syndrome: Description of 9 new cases and beneficial response to bisphosphonates
PMID: 18602879
Gene: LRP5
HGNC: 6697
Disease: osteoporosis-pseudoglioma syndrome
MONDO: 0009820
InheritancePattern: autosomal recessive
Prevalence: osteoporosis-pseudoglioma syndrome is estimated to occur in 1 out of every 2,000,000 live births.
Penetrance: The penetrance of the phenotype among homozygous or compound heterozygous cases appears to be complete, while heterozygous carriers of deleterious variants appear to be mildly affected.
European
Case#: Weisschuh_2020_Patient_MDS_342, male, age 73 years at diagnosis, age 75 years at report, national origin reported as German
CasePresentingHPOs: N/A
CaseHPOFreeText: The patient has been diagnosed with macular dystrophy.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous genotyping consisted of next generation sequencing-based RET.8 panel.
CaseMethod1: next generation sequencing-based RET.8 panel
CaseMethod2: N/A
CaseGenotypingMethod: Genotyping was performed using a next-generation sequencing-based RET.8 panel.
Variant: The patient harbors the NM_001563.4(IMPG1):c.378G>A (p.Trp126Ter) variant in the heterozygous state.
ClinVar: 493439
gnomAD: The NM_001563.4(IMPG1):c.378G>A (p.Trp126Ter) variant is found in gnomAD v2.1.1 at a maximum allele frequency of 0.00006533 (2/30616) in the South Asian population, with no homozygotes https://gnomad.broadinstitute.org/variant/6-76744428-C-T
VariantEvidence: NM_001563.4(IMPG1):c.378G>A (p.Trp126Ter) is a nonsense variant in exon 3 of 17, and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 84% of the protein product.
CaseAddInfo: Segregation confirmation in family members is not available.
CasePMIDs: N/A
A Novel KCNJ13 Nonsense Mutation and Loss of Kir7.1 Channel Function Causes Leber Congenital Amaurosis (LCA16)
PMID: 25921210
Gene: KCNJ13
HGNC: 6259
Disease: Leber congenital amaurosis 16
MONDO: 0013613
InheritancePattern: autosomal recessive
Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns (PMID: 10951519), while the proportion of Leber congenital amaurosis caused by KCNJ13 variants is unknown.
Penetrance: Known disease-causing alleles appear to be completely penetrant.
t
Case#: Haider_2000_Proband_5, female, 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.290G>A (p.Arg97His) variant in the homozygous state.
ClinVarID: 867089
gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.00002441 in the European non-Finnish population (28 alleles / 1147036 total alleles, with 0 homozygotes). https://gnomad.broadinstitute.org/variant/chr15-71811810-G-A?dataset=gnomad_r4
VariantEvidence: NM_014249.4(NR2E3):c.290G>A (p.Arg97His) is a missense variant within the zinc finger / DNA-binding domain of NR2E3,.
CaseAddInfo: The proband comes from a consanguineous family with mother and father being first cousins, and two similarly affected sisters sharing the same homozygous genotype.
CasePMIDs: N/A
In the French family NAL69, we found that the proband (II:4) and his affected sister (II:2) were compound heterozygous for the paternal c.1519C>T mutation in exon 13, leading to the nonsense change p.Arg507∗, and for the maternal c.461T>C mutation in exon 3, leading to the missense change p.Leu154Pro (Figure 4A).
Case#: Manes_2013_Family_NAL69_Proband_II:4, male, age 43 years at time of report, national origin reported as French
CasePresentingHPOs: HP:0007677 (Vitelliform-like macular lesions), HP:0030631 (Hyperautofluorescent macular lesion), HP:0008179 (Decreased Arden ratio of electrooculogram, specifically 1.58 and 1.68 in each eye), HP:0008275 (Abnormal light-adapted electroretinogram, slightly decreased)
CaseHPOFreeText: The patient has been diagnosed with vitelliform macular dystrophy.
CaseNotHPOs: HP:0007663 (Reduced visual acuity), HP:0030469 (Abnormal dark-adapted electroretinogram)
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous testing appears to have been limited to Sanger sequencing-based screening of exon 7 of IMPG1.
CaseMethod1: Sanger sequencing of the 17 exons and flanking intronic sequences
CaseMethod2: N/A
CaseGenotypingMethod: Genotyping appears to have included Sanger-based sequencing of the 17 exons and intronic flanking sequences of the IMPG1 locus.
Variant: The proband harbors the NM_001563.4(IMPG1):c.461T>C (p.Leu154Pro) and NM_001563.4(IMPG1):c.1519C>T (p.Arg507Ter) variants in the compound heterozygous state.
ClinVar: 162136, 162135
gnomAD: The NM_001563.4(IMPG1):c.461T>C (p.Leu154Pro) variant was found in gnomAD v2.1.1 at a frequency of 0.00007924 (9/113576) in the European non-Finnish population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/6-76744345-A-G The NM_001563.4(IMPG1):c.1519C>T (p.Arg507Ter) variant was found in gnomAD v2.1.1 at a frequency of 0.00004007 (1/24958) in the African / African-American population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/6-76660584-G-A?dataset=gnomad_r2_1
VariantEvidence: NM_001563.4(IMPG1):c.461T>C (p.Leu154Pro) is a missense variant that does not have evidence confirming an impact on the gene product. However, another study has reported an apparently unrelated affected patient harboring this variant in the heterozygous state (PMID: 30688845). The NM_001563.4(IMPG1):c.1519C>T (p.Arg507Ter) variant is a nonsense variant in exon 13 of 17 and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 37% of the protein product.
CaseAddInfo: The proband has a similarly affected older sister who shares the same genotype. One carrier child is unaffected while the other has a slight defect in one eye within the line separating the inner and outer segments, consistent with incomplete penetrance in the heterozygous state. Consanguinity is not reported in this family.
CasePMIDs: N/A
RPGR was found in the connecting cilia of rods and cones with no evidence for species-dependent variation. RPGR ORF15 was the predominant variant in photoreceptor connecting cilia whereas constitutive RPGR (default) was the sole variant in the transitional zone of motile cilia in airway epithelia. Removal of soluble materials in the interphotoreceptor matrix facilitated detection of RPGR in the connecting cilia in photoreceptors. conclusions. RPGR localizes in photoreceptor connecting cilia and in a homologous structure, the transitional zone of motile cilia. These data are important for understanding the multitude of clinical manifestations associated with mutations in RPGR.
Selection B - Gene function is consistent with phenotype.
GOterm: GO:0032391 (photoreceptor connecting cilium)
FunctionalEvidence: This study uses a RPGR antibody to stain mouse retinal sections, showing localization of RPGR to the region between the outer segment and inner segment associated with the connecting cilia of rod and cone photoreceptors (Figure 2A). A similar experiment was performed in earlier studies with similar results (PMID: 11104772 Figure 4A, PMID: 10725384 Figure 2D upper). Within mouse airway epithelium tissue sections, RPGR antibody stained a narrow band across the apical domains of multi-ciliated cells (Figure 7A), corresponding with the basal parts of the motile cilia adjacent to the basal bodies (Figures 7B, 7C). This transitional zone of the motile cilia is the structural equivalent of the connecting cilia of photoreceptors, consistent with a biochemical role for RPGR in regulating ciliary organization and/or transport in both the retina and the respiratory tract.
FunctionalHPO: HP:0007642 (Congenital stationary night blindness), HP:0007994 (Peripheral visual field loss), HP:0000529 (Progressive visual loss), HP:0000365 (Hearing impairment), HP:0002205 (Recurrent respiratory infections), HP:0011109 (Chronic sinusitis), HP:0000388 (Otitis media), HP:0002837 (Recurrent bronchitis), HP:0012263 (Immotile cilia), HP:0005938 (Abnormal respiratory motile cilium morphology)
PhenotypeEvidence: This identification of RPGR as a potential regulator of ciliary organization and/or transport in multiple tissues is consistent with the diverse phenotypes associated with RPGR loss-of-function, ranging from visual defects associated with rod and cone dysfunction to respiratory defects associated with dysfunction of the respiratory motile cilia.
A novel recurrent mutation in CFAP47 causes male infertility with asthenoteratozoospermia
PMID: N/A (available only on https://www.authorea.com/)
Gene: CFAP47
HGNC: 26708
Disease: X-linked spermatogenic failure 3
MONDO: MONDO:0025354
InheritancePattern: autosomal recessive
Prevalence: The overall prevalence of male infertility is between 1 in 10 and 1 in 50 males.
Penetrance: Known disease-causing alleles appear to be completely penetrant in hemizygous males.
Lentiviral Expression of Retinal Guanylate Cyclase-1 (RetGC1) Restores Vision in an Avian Model of Childhood Blindness
PMID: 16700630
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
We identified a lineage of rhesus macaques with a frameshift mutation in exon 3 of the BBS7 gene c.160delG (p.Ala54fs) that is predicted to produce a non-functional protein. In humans, mutations in this and other BBS genes cause Bardet-Biedl syndrome, a ciliopathy and a syndromic form of retinitis pigmentosa generally occurring in conjunction with kidney dysfunction, polydactyly, obesity, and/or hypogonadism. Three full- or half-sibling monkeys homozygous for the BBS7 c.160delG variant, at ages 3.5, 4 and 6 years old, displayed a combination of severe photoreceptor degeneration and progressive kidney disease. In vivo retinal imaging revealed features of severe macular degeneration, including absence of photoreceptor layers, degeneration of the retinal pigment epithelium, and retinal vasculature atrophy. Electroretinography in the 3.5-year-old case demonstrated loss of scotopic and photopic a-waves and markedly reduced and delayed b-waves. Histological assessments in the 4- and 6-year-old cases confirmed profound loss of photoreceptors and inner retinal neurons across the posterior retina, with dramatic thinning and disorganization of all cell layers, abundant microglia, absent or displaced RPE cells, and significant gliosis in the subretinal space. Retinal structure, including presence of photoreceptors, was preserved only in the far periphery. Ultrasound imaging of the kidneys revealed deranged architecture, and renal histopathology identified distorted contours with depressed, fibrotic foci and firmly adhered renal capsules; renal failure occurred in the 6-year-old case. Magnetic resonance imaging obtained in one case revealed abnormally low total brain volume and unilateral ventricular enlargement. The one male had abnormally small testes at 4 years of age, but polydactyly and obesity were not observed.
ExperimentName: Naturally occurring BBS7 loss-of-function primate model
NonHumanModel: Rhesus macaque
GeneAlteration: The model animals harbor a naturally occurring homozygous frameshift variant at nucleotide 160 within exon 3 of the BBS7 locus.
ModelPhenotype: HP:0000608 (Macular degeneration), HP:0030609 (Photoreceptor layer loss on macular OCT), HP:0000580 (Pigmentary retinopathy), HP:0008046 (Abnormal retinal vascular morphology), progressive kidney disease, HP:0030483 (Reduced amplitude of dark-adapted bright flash electroretinogram a-wave), HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0008275 (Abnormal light-adapted electroretinogram), HP:0002171 (Gliosis), HP:0000083 (Renal insufficiency), HP:0012210 (Abnormal renal morphology), HP:0002119 (Ventriculomegaly), HP:0008734 (Decreased testicular size)
HumanPhenotype: HP:0001956 (Truncal obesity), HP:0000618 (Blindness), HP:0001249 (Intellectual disability), HP:0001631 (Atrial septal defect), HP:0001640 (Cardiomegaly), HP:0100598 (Pulmonary edema), HP:0012584 (Bilateral renal hypoplasia), HP:0004719 (Hyperechogenic kidneys), HP:0003774 (Stage 5 chronic kidney disease), HP:0000580 (Pigmentary retinopathy), HP:0000648 (Optic atrophy), HP:0008043 (Retinal arteriolar constriction), HP:0007737 (Bone spicule pigmentation of the retina), HP:0007754 (Macular dystrophy)
ModelEvidence: This is a naturally occurring Rhesus macaque model of biallelic BBS7 disruption. The mutant animals exhibit hypoechoic kidney lesions (Figure 1), retinal atrophy with lack of retinal vasculature (Figure 3A), RPE atrophy (Figure 3B), severe atrophy of retinal layers by OCT with greater severity centrally (Figure 3C), retinal gliosis (Figure 3D), Severely reduced amplitudes and delayed time courses of both dark-adapted and light-adapted flicker ERG (Figure 4), reduced brain volume (Figure 5B), dilation of the lateral ventricle (Figure 5A), cystic kidney tubules with loss of nephrons replaced with fibrosis, tubule atrophy, and ectasia (Figure 7), reduced size and histological maturity of testes (Table 1), and vision deficits (Table 1).
ModelVariant: This model did not introduce a disease-associated variant known from an affected human patient, but rather studied a naturally occurring and apparent null variant disrupting BBS7 expression.
Novel GPR143 mutations and clinical characteristics in six Chinese families with X-linked ocular albinism
PMID: 18978956
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.
Hypoxia-regulated components of the U4/U6.U5 tri-small nuclear riboprotein complex: possible role in autosomal dominant retinitis pigmentosa
PMID: 18334927
Pathogenic variants in IMPG1 cause autosomal dominant and autosomal recessive retinitis pigmentosa
PMID: 32817297
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.
Identification of a novel GPR143 mutation in a large Chinese family with congenital nystagmus as the most prominent and consistent manifestation
PMID: 17516023
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.
p.S89F
Case#: Liu_2007_Family_Patient_V-10, male, age <6 months at time of onset, family origin reported to be Chinese
CasePresentingHPOs: HP:0006934 (Congenital nystagmus), HP:0000666 (Horizontal nystagmus), HP:0007750 (Hypoplasia of the fovea), HP:0000483 (Astigmatism), HP:0007663 (Reduced visual acuity), HP:0007814 (Retinal pigment epithelial mottling), HP:0000646 (Amblyopia)
CaseHPOFreeText: The proband and his affected family members have been diagnosed with congenital nystagmus segregating with an X-linked mode of inheritance.
CaseNotHPOs: HP:0001000 (Abnormality of skin pigmentation), HP:0009887 (Abnormality of hair pigmentation), HP:0012805 (Iris transillumination defect), HP:0007894 (Hypopigmentation of the fundus), HP:0000545 (Myopia)
CaseNotHPOFreeText: The patient did not exhibit abnormalities of the optic nerve head on functional MRI.
CasePreviousTesting: Linkage mapping has been performed in affected and unaffected family members using 33 polymorphic markers along the entire X chromosome. Haplotype analysis identified a shared region of approximately 10.6 Mb in all affected males.
CaseMethod1: Linkage mapping and haplotype analysis
CaseMethod2: Sanger sequencing of 21 candidate genes in the linkage region
CaseGenotypingMethod: Linkage mapping has been performed in the proband and affected and unaffected family members using 33 polymorphic markers along the entire X chromosome. Haplotype analysis identified a shared region of approximately 10.6 Mb in all affected males. Sanger sequencing was then performed for 21 candidate genes in the linkage region, followed by RFLP analysis in a subset of affected and unaffected family members.
Variant: The proband harbors the NM_000273.3(GPR143):c.266C>T (p.Ser89Phe) variant in the hemizygous state.
ClinVar: 10522
gnomAD: This variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_000273.3(GPR143):c.266C>T (p.Ser89Phe) is a missense variant in exon 2 of 9 total, and is located in a transmembrane domain but does not have experimental evidence of gene impact.
CaseAddInfo: The proband is from a family with at least four other affected males and one affected female family member who also harbor the variant.
CasePMIDs: N/A
intragenic deletions
Case#: Xin_Patient_5, sex not mentioned, age 17 at onset, U.S. nationality, admixed European non-Finnish ethnicity
CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0003581 (Adult onset), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material)
CaseHPOFreeText: Motor difficulty was the phenotype at presentation (age 17). Visual loss (age 18), Cognitive regression (age 25), and seizure (age 18) subsequently developed. Granular type inclusions were observed in blood by electron microscopy. Fingerprint inclusions were observed in the brain.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.
CaseMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing.
CaseMethod2: as mentioned
CaseGenotypingMethod: CLN5 genotyping was performed by PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.
Variant: The patient harbors the NM_006493.4(CLN5):c.974A>G (p.Tyr325Cys) variant as well as a chromosomal deletion that includes exon 4.
ClinVar: 2570 (in trans with exon 4 deletion with undefined boundaries)
gnomAD: Maximum allele frequency for NM_006493.4(CLN5):c.974A>G (p.Tyr325Cys) is 0.00002784 (in the European non-Finnish population, no homozygotes). https://gnomad.broadinstitute.org/variant/13-77575001-A-G
VariantEvidence: The variant encodes a missense substitution that adds a cysteine to the CLN5 protein and may disrupt its structure. In a previous publication from an overlapping group of authors, mass spectrometry confirmed absence of CLN5 protein expression in samples from an individual harboring this variant, but in not control samples (PMID:19383612).
CaseAddInfo: Although parents do not appear to have been genotyped, the missense variant (in exon 4) can be inferred to be in trans with the exon 4 deletion.
CasePMIDs: N/A
missense
Case#: Xin_Patient_3, sex not mentioned, age 17 at onset, U.S. nationality, admixed European non-Finnish ethnicity
CasePresentingHPOs: HP:0004302 (Functional motor deficit), HP:0000572 (Visual loss), HP:0001250 (Seizure), HP:0001268 (Mental deterioration), HP:0003581 (Adult onset), HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0003226 (Rectilinear intracellular accumulation of autofluorescent lipopigment storage material)
CaseHPOFreeText: Cognitive regression was the phenotype at presentation (age 17). Visual loss (age 20), motor difficulty (age 23), and seizure (age 23) subsequently developed. Granular type inclusions were observed by electron microscopy. Fingerprint inclusions were observed in the skin, rectilinear inclusions were observed in the muscle, and curvilinear inclusions were observed in neurons, glial cells, muscle, and spleen.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous testing for mutations in the CLN1, CLN2, CLN3, CLN6, and CLN8 had already occurred, using PCR amplification and Sanger sequencing to exclude the possibility of variants in the exons and surrounding noncoding regions. Genome-wide analysis methods were not used, as NCL had already been diagnosed based on clinical phenotypes.
CaseMethod1: PCR amplification of the coding and surrounding non-coding regions of each gene, followed by bidirectional Sanger sequencing
CaseMethod2: as mentioned
CaseGenotypingMethod: CLN5 genotyping was performed by PCR amplification of the four exons and surrounding non-coding regions was performed, followed by bi-directional Sanger sequencing. Synthetic multiplex ligation-dependent probe amplification (MLPA) was then used to calculate average gene dosage ratio for each ratio, in order to detect large deletions.
Variant: The patient harbors the NM_006493.4(CLN5):c.230G>A (p.Cys77Tyr) and NM_006493.4(CLN5):c.974A>G (p.Tyr325Cys) variants.
ClinVar: 2569, 2570
gnomAD: The NM_006493.4(CLN5):c.230G>A (p.Cys77Tyr) variant is not found in gnomAD. Maximum allele frequency for NM_006493.4(CLN5):c.974A>G (p.Tyr325Cys) is 0.00002784 (in the European non-Finnish population, no homozygotes). https://gnomad.broadinstitute.org/variant/13-77575001-A-G
VariantEvidence: Both variants encode missense substitutions in the protein product. Because both change the total number of cysteines in the CLN5 protein, they may disrupt its structure. In a previous publication from an overlapping group of authors, mass spectrometry confirmed absence of CLN5 protein expression in samples from this individual, but in not control samples (PMID:19383612).
CaseAddInfo: Parents do not appear to have been genotyped, so it is not clear whether the two variants are confirmed to be in trans.
CasePMIDs: 19383612
CLN5 mutations are frequent in juvenile and late-onset non-Finnish patients with NCL
PMID: 20157158
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
c.889C->T
Case#: Riazuddin_2006_Family_61019_patient_20, female, age 18 years at time of study, Pakistani family origin from remote Punjab province
CasePresentingHPOs: HP:0000543 (Optic disc pallor), HP:0007843 (Attenuation of retinal blood vessels), HP:0007737 (Bone spicule pigmentation of the retina), HP:0000550 (Undetectable electroretinogram)
CaseHPOFreeText: The proband and her affected family members have been diagnosed with autosomal recessive retinitis pigmentosa.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Genome-wide linkage analysis, with maximum LOD score associated with the D5S2015 microsatellite marker on chromosome 5q31-33.
CaseMethod1: Genome-wide linkage analysis
CaseMethod2: Sanger sequencing of the candidate gene PDE6A
CaseGenotypingMethod: Genome-wide linkage analysis was initially performed on all four families, with maximum LOD score associated with the D5S2015 microsatellite marker on chromosome 5q31-33. Sanger sequencing was then performed on PCR products of exons and flanking regions from the PDE6A candidate locus.
Variant: The affected members of Family 61019 harbor the NM_000440.3(PDE6A):c.769C>T (p.Arg257Ter) variant in the homozygous state.
ClinVar: 437984
gnomAD: In gnomAD v2.1.1, NM_000440.3(PDE6A):c.769C>T (p.Arg257Ter) has a frequency of 0.0001633 (5/30612) in the South Asian population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/5-149310680-G-A
VariantEvidence: NM_000440.3(PDE6A):c.769C>T (p.Arg257Ter) is a nonsense variant in exon 4 of 22 that is predicted to trigger nonsense-mediated decay or at least to truncate ~70% of the protein product.
CaseAddInfo: The patient is from a family with consanguineous unions.
CasePMIDs: N/A
Cellular ciliary phenotyping indicates pathogenicity of novel variants in IFT140 and confirms a Mainzer–Saldino syndrome diagnosis
PMID: 30479745
Gene: IFT140
HGNC: 29077
Disease: Short-rib thoracic dysplasia 9 with or without polydactyly
MONDO: 0009964
InheritancePattern: autosomal recessive
Prevalence: Within the lumped disease entity for this curation, the most prevalent form may be retinitis pigmentosa. The prevalence of Saldino-Mainzer syndrome (one of the synonyms of Short-rib thoracic dysplasia 9) is less than 1 in 1,000,000. The prevalence of Leber congenital amaurosis cases caused by IFT140 variants (PMID: 26216056) is calculated to be less than 1 in 3,000,000. Although IFT140 variants are estimated to be responsible for less than 2% of RP, the prevalence of the overall disorder at 1 in 3,000 or 1 in 4,000 means the frequency of these cases could potentially be higher than 1 in 1,000,000.
Penetrance: Known variants for this lumped disease entity appear to be completely penetrant, with highly variable phenotypes and age of onset. On the other hand, the split disease entity caused by monoallelic IFT140 variants appears to have incomplete penetrance.
BBS7 is required for BBSome formation and its absence in mice results in Bardet-Biedl syndrome phenotypes and selective abnormalities in membrane protein trafficking
PMID: 23572516
Gene: BBS7
HGNC: 18758
Disease: Bardet-Biedl syndrome 7
MONDO: 0014435
InheritancePattern: autosomal recessive
Prevalence: The prevalence of BBS7 variants among Bardet-Biedl syndrome cohorts has been reported at 4.2% (PMID: 19402160), while the prevalence of Bardet-Biedl syndrome overall has been estimated between 1 in 13,500 and 1 in 160,000 live births, depending on the population (PMID: 22713813).
Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.
We identified C. reinhardtii mutants for BBS1, -4, and -7; they have full-length flagella, and IFT is unaffected. Collectively, the results indicate that the BBSome is carried by IFT but is not an integral component of the IFT machinery.All three BBS mutants are nonphototactic. Biochemical analyses of flagellar fractions of the BBS mutants revealed that several proteins associated with the flagellar membrane and matrix and likely to be involved in signal transduction are abnormally accumulated in the flagella; this apparently impairs the ability of the organelle to carry out phototactic steering
ExperimentName: bbs1-1 Chlamydomonas have full-length flagella and normal IFT function but are nonphototactic.
NonHumanModel: Chlamydomonas reinhardtii
GeneAlteration: The bbs1-1 model animals have been identified as naturally occurring mutants with deletion of approximately half of the BBS1 gene as well as a separate gene unstream of BBS1.
ModelPhenotype: abnormal flagellar motility (inability to perform phototaxis), flagellar absence of BBSome components (specifically BBS4)
HumanPhenotype: HP:0000639 (Nystagmus), HP:0000510 (Rod-cone dystrophy), HP:0007663 (Reduced visual acuity), HP:0000662 (Nyctalopia), HP:0000518 (Cataract), HP:0008323 (Abnormal light- and dark-adapted electroretinogram), HP:0000107 (Renal cyst), HP:0001513 (Obesity), HP:0010442 (Polydactyly), HP:0002463 (Language impairment), HP:0000026 (Male hypogonadism)
ModelEvidence: The mutants lack the ability to perform phototaxis, which is common among all BBSome mutants tested (described in text but data not shown). Flagella from the mutant show loss of BBS4 localization (Figure 4C). However, flagellar length was normal (Figure 2B) and flagellar regeneration was normal as well (described in text but data not shown).
ModelVariant: This model had a naturally occurring deletion disrupting BBS1 but did not feature knock-in of a known variant from the human patient population.
Mutations in the human retinal degeneration slow (RDS) gene can cause either retinitis pigmentosa or macular dystrophy
PMID: 8485576
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).
Novel mutations affecting LRP5 splicing in patients with osteoporosis-pseudoglioma syndrome (OPPG)
PMID: 21407258
Gene: LRP5
HGNC: 6697
Disease: osteoporosis-pseudoglioma syndrome
MONDO: 0009820
InheritancePattern: autosomal recessive
Prevalence: osteoporosis-pseudoglioma syndrome is estimated to occur in 1 out of every 2,000,000 live births.
Penetrance: The penetrance of the phenotype among homozygous or compound heterozygous cases appears to be complete, while heterozygous carriers of deleterious variants appear to be mildly affected.
Retention of lysosomal protein CLN5 in the endoplasmic reticulum causes neuronal ceroid lipofuscinosis in Asian Sibship
PMID: 19309691
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
E1270fs
Case#: Gong_2001_Proband_6, no reported gender, age or national origin
CasePresentingHPOs: HP:0004349 (Reduced bone mineral density)
CaseHPOFreeText: The proband has been diagnosed with osteoporosis-pseudoglioma syndrome segregating with an autosomal recessive mode of inheritance. This implies a combination of ophthalmologic and radiographic features, but these have not been described in detail.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Genome-wide linkage mapping with 160 SSRP markers was performed on three different consanguineous kindreds (from Finland, South Africa, and Italy) (fig. 1), but it is not clear whether this proband was a member of one of these kindreds.
CaseMethod1: Linkage analysis with additional markers around a strong candidate marker
CaseMethod2: Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 locus
CaseGenotypingMethod: Genotyping appears to have been limited to Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 locus.
Variant: The patient harbors the NM_002335.4(LRP5):c.3804del (p.Glu1270fs) variant in the homozygous state.
ClinVar: 6273
gnomAD: The NM_002335.4(LRP5):c.3804del (p.Glu1270fs) variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_002335.4(LRP5):c.3804del (p.Glu1270fs) is a frameshift variant in exon 18 out of 23 that is predicted to trigger nonsense-mediated decay or at least to truncate the C-terminal ~21% of the protein product. It appears to be stable at the protein level but is not secreted in the exogenous expression system, consistent with loss-of-function rather than dominant negative effect.
CaseAddInfo: The family is reportedly consanguineous.
CasePMIDs: PMID: 8659519
homozygous frameshift
Case#: Gong_2001_Proband_1, no reported gender, age or national origin
CasePresentingHPOs: HP:0004349 (Reduced bone mineral density)
CaseHPOFreeText: The proband has been diagnosed with osteoporosis-pseudoglioma syndrome segregating with an autosomal recessive mode of inheritance. This implies a combination of ophthalmologic and radiographic features, but these have not been described in detail.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Genome-wide linkage mapping with 160 SSRP markers was performed on three different consanguineous kindreds (from Finland, South Africa, and Italy) (fig. 1), but it is not clear whether this proband was a member of one of these kindreds.
CaseMethod1: Linkage analysis with additional markers around a strong candidate marker
CaseMethod2: Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 locus
CaseGenotypingMethod: Genotyping appears to have been limited to Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 locus.
Variant: The patient harbors the NM_002335.4(LRP5):c.29G>A (p.Trp10Ter) variant in the homozygous state.
ClinVar: 6268
gnomAD: The NM_002335.4(LRP5):c.29G>A (p.Trp10Ter) variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_002335.4(LRP5):c.29G>A (p.Trp10Ter) is a nonsense variant in exon 1 out of 23 that is predicted to trigger nonsense-mediated decay or at least to truncate the C-terminal ~99% of the protein product.
CaseAddInfo: The family is reportedly consanguineous.
CasePMIDs: PMID: 8659519
Four affected members of a Swedish family were included. Three of them were examined with best corrected visual acuity, Goldmann perimetry, full-field-and multifocal electroretinography, optical coherence tomography, fundus color photographs, fundus autofluorescence images, slit lamp inspection, and genetic testing. The fourth subject only managed genetic testing. Results: All subjects carry the pathogenic missense variant; c.484C>T (NM_002242.4), R162W, in KCNJ13. ERG measurements revealed reduced macular-as well as general retinal function. Two of the subjects had a history of retinal detachment and the two younger subjects demonstrated early onset cataract. They all had structural macular changes and slightly gliotic optic discs.
Case#: Schroeder_2022_Proband, female, age 32 at time of diagnosis, family national origin reported as Swedish
CasePresentingHPOs: Optic disc pallor HP:0000543, Retinal detachment HP:0000541, Presenile cataracts HP:0007819, Decreased light- and dark-adapted electroretinogram amplitude HP:0000654, Retinal hole HP:0011530, Abnormal fundus autofluorescence imaging HP:0030602
CaseHPOFreeText: The patient optic discs were described as slightly gliotic. OCT showed lacunar retinal substance losses in the fovea and attenuation in all segments of the macula. FAF showed a paracentral ring of fine granular increase of autofluorescence around the fovea in the posterior pole.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Genotyping of the proband was performed by whole genome sequencing.
CaseMethod1: whole genome sequencing
CaseMethod2: Sanger sequencing of KCNJ13
CaseGenotypingMethod: Genotyping of the proband was performed by whole genome sequencing, followed by Sanger sequencing of KCNJ13.
Variant: The individual harbors the NM_002242.4(KCNJ13):c.484C>T (p.Arg162Trp) variant in the heterozygous state.
ClinVar: 6585
gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.0000008536 (1 / 1,171,470) in the European (non-Finnish) population https://gnomad.broadinstitute.org/variant/chr2-232768790-G-A?dataset=gnomad_r4
VariantEvidence:NM_002242.4(KCNJ13):c.484C>T (p.Arg162Trp) is a missense variant that has functional evidence of electrophysiological abnormalities and loss of sensitivity to different K+ concentrations, when exogenously expressed in CHO cells (PMID: 18179896, Figure 2).
CaseAddInfo: The proband has three affected family members who also harbored the variant in the heterozygous state. Consanguinity was not reported.
CasePMIDs: N/A
We detected novel missense changes in individual patients in the sequence of the genes PRPF4 and EFTUD2, but the role of these changes in relationship to disease could not be verified.
Case#: Benaglio_2014_Proband_001-417, sex not reported, age not reported, national origin German
CasePresentingHPOs: N/A
CaseHPOFreeText: The proband has been diagnosed with autosomal dominant retinitis pigmentosa.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous testing in the proband consisted of screening either by Sanger sequencing of 90% of known adRP genes, by genotyping microarray of known RP variants, or sequencing-based genotyping of RHO, RDS, PRPF31, RP1, PRPF8, IMPDH1, NRL, PRPF3, NR2E3, and SNRNP200.
CaseMethod1: next-generation sequencing of PRPF4 and EFTUD2 genes
CaseMethod2: Sanger sequencing of the coding regions of NHP2L1 and AAR2
CaseGenotypingMethod: Genotyping of the proband initially consisted of either Sanger sequencing of 90% of known adRP genes, genotyping microarray of known RP variants, or sequencing-based genotyping of RHO, RDS, PRPF31, RP1, PRPF8, IMPDH1, NRL, PRPF3, NR2E3, and SNRNP200. Subsequent genotyping was performed by next-generation sequencing of PRPF4 and EFTUD2 genes and Sanger sequencing of the coding regions of NHP2L1 and AAR2.
Variant: The proband harbors the NM_001244926.2(PRPF4):c.556C>G (p.Pro186Ala) variant in the heterozygous state.
ClinVar ID: 865751
gnomAD: The NM_001244926.2(PRPF4):c.556C>G (p.Pro186Ala) variant is found in gnomAD v4.1.0 at a frequency of 0.00006609 (90 alleles / 1180038 total alleles, with 0 homozygotes) in the European (non-Finnish) population https://gnomad.broadinstitute.org/variant/9-113283207-C-G?dataset=gnomad_r4
VariantEvidence: NM_001244926.2(PRPF4):c.556C>G (p.Pro186Ala) is a missense variant located 5 bp from the 3' end of exon 5 with no direct evidence of an abnormal impact on the PRPF4 protein.
CaseAddInfo: The proband has an affected sibling who also harbors the variant.
CasePMIDs: N/A
EYS Is a Protein Associated with the Ciliary Axoneme in Rods and Cones
PMID: 27846257
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.
Recessive Mutations in KCNJ13, Encoding an Inwardly Rectifying Potassium Channel Subunit, Cause Leber Congenital Amaurosis
PMID: 21763485
Gene: KCNJ13
HGNC: 6259
Disease: Leber congenital amaurosis 16
MONDO: 0013613
InheritancePattern: autosomal recessive
Prevalence: The overall prevalence of Leber congenital amaurosis is between 1 in 33,000 and 1 in 100,000 newborns (PMID: 10951519), while the proportion of Leber congenital amaurosis caused by KCNJ13 variants is unknown.
Penetrance: Known disease-causing alleles appear to be completely penetrant.
Morpholino-mediated knockdown of OA1 (also known as GPR143), mutations in the human homologue of which cause the most common form of human ocular albinism, induces a major reduction in melanosome number, recapitulating a key feature of the mammalian disease where reduced melanosome numbers precede macromelanosome formation.
ExperimentName: Zebrafish knockdown of the GPR143 ortholog OA1
NonHumanModel: Danio rerio
GeneAlteration: A zebrafish model of OA1 loss-of-function was generated by morpholino-based knockdown.
ModelPhenotype: HP:0007703 (Abnormality of retinal pigmentation)
HumanPhenotype: HP:0000639 (Nystagmus), HP:0003593 (Infantile onset), HP:0007663 (Reduced visual acuity), HP:0001361 (Nystagmus-induced head nodding), HP:0000646 (Amblyopia), HP:0000483 (Astigmatism), HP:0000613 (Photophobia), normally pigmented skin and hair, HP:0005592 (Giant melanosomes in melanocytes), HP:0007750 (Hypoplasia of the fovea), HP:0007894 (Hypopigmentation of the fundus), HP:0025551 (Optic nerve misrouting)
ModelEvidence: The zebrafish match one feature of the human patients in that they exhibit abnormalities of retinal pigmentation consistent with the ability of GPR143 loss-of-function to trigger defects in melanosome regulation (Figure 1).
ModelVariant: This model features disruption of OA1 expression by knockdown, and does not harbor a mutation equivalent to a variant from a human patient.
The other patient, SRF92, is an 11-year-old male diagnosed with LCA/early onset severe retinal dystrophy. His fundus image showed extensive retinal pigment crumbs including macula region and OCT results indicated IS/OS loss and retinal atrophy (Fig. 1). According to Sanger sequencing, this patient inherited a frameshift variant (c.1655_1656delAG, p.E522Gfs*6) from his father and a missense variant (c.G2368A, p.E790K) from his mother (Fig. 2). Both variants are extremely rare in control individuals (less than 1 in 60,000). Similar to previously described variants, the E790 K variant affects a conserved AA site and predicted to be damaging by five out of six algorithms. This patient also does not show typical MZSDS or JATD-like syndromic phenotypes but has hypogonadism and mild fatty liver disease (Table 1, Table S3).
Case#: Xu_2012_Patient_SRF92, male, 11 years of age at time of study, of Chinese ethnicity
CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000556 (Retinal dystrophy), HP:0000580 (Pigmentary retinopathy), HP:0030609 (Photoreceptor layer loss on macular OCT), HP:0001105 (Retinal atrophy), HP:0000026 (Male hypogonadism)
CaseHPOFreeText: This proband was diagnosed with Leber congenital amaurosis, and has mild fatty liver disease.
CaseNotHPOs: HP:0000924 (Abnormality of the skeletal system), HP:0000077 (Abnormality of the kidney)
CaseNotHPOFreeText: N/A
CasePreviousTesting: It is not clear whether the patient was previously subjected to genotyping.
CaseMethod1: Whole exome sequencing
CaseMethod2: Sanger sequencing of IFT140
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_014714.3(IFT140):c.1655_1656del (p.Glu522Glyfs6) and maternal NM_014714.3(IFT140):c.2368G>A (p.Glu790Lys) variants in IFT140*.
CAID: CA2201732453, CA7813927
gnomAD: The NM_014714.3(IFT140):c.1655_1656del (p.Glu522Glyfs*6) variant was not found in gnomAD. The NM_014714.3(IFT140):c.2368G>A (p.Glu790Lys) variant is present in gnomAD at a frequency of 0.0001087 in the East Asian population (2/18394, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1607967-C-T
VariantEvidence: NM_014714.3(IFT140):c.1655_1656del (p.Glu522Glyfs*6) is a frameshift variant that introduces a premature stop codon in exon 15/31 and is predicted to trigger NMD or at least to truncate ~64% of the protein product. NM_014714.3(IFT140):c.2368G>A (p.Glu790Lys) is a missense variant that does not have functional evidence of gene impact.
CaseAddInfo: The proband's parents are each heterozygous for one variant.
CasePMIDs: N/A
The index case we investigated, SRF71, is a 43-year-old male RP patient of Han Chinese ethnicity. He was aware of night blindness during childhood and vision loss at the age of 36 (Table 1). His fundus images showed widespread retinal bone spicule pigmentation, and gold foil macular reflex. OCT images showed loss of inner segment (IS)/outer segment (OS) of photoreceptor cells (Fig. 1). His parents are normal and he has an unaffected sister. Preliminary screening by retinal capture sequencing found no causative mutations in known RP-causing genes. WES data show that he has biallelic variants in IFT140, including a missense (c.T4196C, p. L1399P) and a frameshift (c. 1898_1901delATAA, p. N633Sfs*10) variant. Neither variant was found more than once in ExAC controls (Table 1). The missense variant disrupts a highly conserved amino acid (AA) in TPR9 domain and is considered to be damaging by 5 out of 6 prediction algorithms (Fig. 3; Table S2). The frameshift variant does not lie in the last exon thus it probably leads to a nonsense-mediated decay of the IFT140 transcript. Sanger sequencing confirmed his unaffected sister is wild type at these two alleles and his parents possess one IFT140 variant each, supporting the pathogenicity of the IFT140 variants (Fig. 2). Given that IFT140 is associated with syndromic ciliopathies, we performed radiography of skeletons and laboratory tests for hepatic and renal functions. Interestingly, the patient does not show any other symptoms or abnormalities after detailed examination (Figure S4, Table S3). Therefore, these results raise the possibility that mutations in IFT140 might lead to non-syndromic retinal disease.
Case#: Xu_2012_Patient_SRF71, male, 43 years of age at time of study, of Han Chinese ethnicity
CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000662 (Nyctalopia), HP:0000572 (Visual loss), HP:0007737 (Bone spicule pigmentation of the retina), HP:0030609 (Photoreceptor layer loss on macular OCT)
CaseHPOFreeText: This proband was diagnosed with retinitis pigmentosa.
CaseNotHPOs: HP:0000924 (Abnormality of the skeletal system), HP:0001410 (Decreased liver function), HP:0000077 (Abnormality of the kidney)
CaseNotHPOFreeText: N/A
CasePreviousTesting: The patient was previously subjected to retinal capture sequencing focused on genes known to be associated with retinitis pigmentosa, without detecting suspected pathogenic variants.
CaseMethod1: Whole exome sequencing
CaseMethod2: Sanger sequencing of IFT140
CaseGenotypingMethod: Following the failure of retinal capture sequencing to identify retinitis pigmentosa gene variants, 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.1898_1901del (p.Asn633fs) and maternal NM_014714.4(IFT140):c.4196T>C (p.Leu1399Pro) variants in IFT140.
ClinVar: 446312, 446311
gnomAD: The NM_014714.4(IFT140):c.1898_1901del (p.Asn633fs) variant was not found in gnomAD. The NM_014714.4(IFT140):c.4196T>C (p.Leu1399Pro) variant is present in gnomAD at a frequency of 0.0001578 in the East Asian population (3/19014, with no homozygotes) https://gnomad.broadinstitute.org/variant/16-1561138-A-G
VariantEvidence: NM_014714.4(IFT140):c.1898_1901del (p.Asn633fs) is a frameshift variant that introduces a premature stop codon in exon 16/31 and is predicted to trigger NMD or at least to truncate ~57% of the protein product. NM_014714.4(IFT140):c.4196T>C (p.Leu1399Pro) is a missense variant that does not have functional evidence of gene impact.
CaseAddInfo: The proband's parents are each heterozygous for one variant, while his unaffected sister does not harbor a variant.
CasePMIDs: N/A
Sequence analysis of ADAM9 in affected and carrier GITs revealed a deletion of exons 15 and 16 which alters the reading frame leading to a premature stop codon. This mutation was absent from 34 other dog breeds. A variable and, at times, very late onset of gPRA was confirmed in GITs by a relatively mild retinal degeneration at an advanced age. Hence, the identification of the genetic defect underlying gPRA in the GIT represents a suitable model for cone-rod dystrophy of humans, with superior potential to elucidate functional consequences of the recently described null mutations in the human ADAM9 gene.
ExperimentName: Canine model of Adam9 loss-of-function
NonHumanModel: Canis lupus familiaris
GeneAlteration: The affected dogs have homozygous disruption of the Adam9 gene by a deletion of regions from exons 15 and 16.
ModelPhenotype: HP:0001105 (Retinal atrophy), HP:0000529 (Progressive visual loss), HP:0000580 (Pigmentary retinopathy), HP:0000662 (Nyctalopia)
HumanPhenotype: HP:0011463 (Childhood onset), HP:0000548 (Cone/cone-rod dystrophy), 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)
ModelEvidence: The affected dogs have been described as having generalized progressive retinal atrophy. Complete loss of all retinal layers was observed in affected animals (Figures 1H-1P). This matches the mode of inheritance and progressive nature of the human disease state, as well as the retinal abnormalities and visual defects.
ModelVariant: The model harbors a targeted deletion that does not have an equivalent / orthologous variant reported in human patients.
In cell-based assays, the overexpression of ADAM9 enhanced the ectodomain shedding of EphB4, Tie-2, Flk-1, CD40, VCAM, and VE-cadherin, so the enhanced expression of ADAM9 could potentially affect pathological neovascularization by increasing the shedding of these and other membrane proteins from endothelial cells. Finally, we provide the first evidence for the upregulation of ADAM9-dependent shedding by reactive oxygen species, which in turn are known to play a critical role in OIR.
Selection B- Gene function is consistent with phenotype.
Title: ADAM9 enhances protelytic shedding of membrane protein ectodomains.
GOterm: GO:0006509 (membrane protein ectodomain proteolysis), GO:0045765 (regulation of angiogenesis)
FunctionalEvidence: ADAM9 over-expression in COS-7 cells enhances proteolytic shedding of membrane proteins involved in angiogenesis (Figure 5). This effect is further enhanced by reactive oxygen species (Figures 6, 7).
FunctionalHPO: HP:0007843 (Attenuation of retinal blood vessels), HP:0000546 (Retinal degeneration)
PhenotypeEvidence: This evidence is consistent with attenuation of retinal blood vessels observed in human patients as well as the finding from this same paper that Adam9 knockout mice exhibit reduced ocular neovascularization (Figures 1, 3).
The non-snRNP factors are also necessary for splicing, of which serine/arginine (SR)-rich proteins were considered as markers of splicing speckles (25). We determined whether p.Pro315Leu could affect the pattern of splicing speckles using SC-35, a non-snRNP component, as a marker (25). We performed immunofluorescence and Q-PCR on cells carrying either p.Pro315Leu or WT allele. By confocal microscopy, we found the level of endogenous SC-35 is dramatically increased with a diffused pattern in hPrp4Pro315Leu fibroblasts, whereas in control fibroblasts the SC-35 showed a distinctly speckled pattern (Fig. 4B and C). Consistently, Q-PCR revealed that the expression levels of SRSF1 (encoding SF2/ASF; NM_006924.4), another non-snRNP component and SRSF2 (encoding SC-35; NM_003016.4) were significantly increased in hPrp4Pro315Leu fibroblasts compared with WT fibroblasts (Fig. 4A). Similar changes in the levels and distribution of SC-35 were also observed in ARPE19 and 293T cells transfected with hPrp4Pro315Leu, but not in those transfected with hPrp4WT (Fig. 4D–G), indicating that the p.Pro315Leu variant of PRPF4 affected the splicing machinery.
ExperimentName: Altered pattern of splicing speckles in patient fibroblasts harboring a heterozygous p.Pro315Leu variant in PRPF4
PatientCell: CL:0000057 (fibroblast)
GeneFunction: GO:0000398 (mRNA splicing, via spliceosome)
GeneAlteration: Cells harbor a heterozygous p.Pro315Leu variant in PRPF4.
FunctionalEvidence: Patient cells harboring the variant exhibit a much higher level of endogenous marker of splicing speckles (SC-35) with a diffused distribution rather than a pattern of distinct speckles (Figures 4B and 4C). RT-PCR showed increased expression of SRSF1 and SRSF2 as well (Figure 4A). Collectively, the patient cells harboring the variant show molecular evidence of disrupted splicing.
FAVariants: The model harbors the NM_001244926.2(PRPF4):c.941C>T (p.Pro314Leu) variant in the heterozygous state (ClinVar ID: 143057).
in the TIMP3 gene
Case: Weber_1994_Family_M_Patient_IV-2, male, age 28 at onset of symptoms
DiseaseAssertion: Sorsby's fundus dystrophy
FamilyInfo:
CasePresentingHPOs: HP:0011506 (Choroidal neovascularization), HP:0025094 (Disciform macular scar), HP:0007663 (Reduced visual acuity), HP:0000819 (Diabetes mellitus), HP:0007703 (Abnormality of retinal pigmentation), HP:0012805 (Iris transillumination defect), HP:0012231 (Exudative retinal detachment), HP:0030604 (Abnormal fundus fluorescein angiography), HP:0011506 (Choroidal neovascularization), HP:0000603 (Central scotoma), HP:0000654 (Decreased light- and dark-adapted electroretinogram amplitude)
CaseHPOFreeText: 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. Granularity / abnormalities of the RPE were present in both eyes and preceded the onset of visual problems in the initially-unaffected eye. Serous detachment of sensory retina had underlying pigment epithelial detachment. CNV was accompanied by leakage from foveal avascular zone. Loss of visual acuity was progressive but possibly stabilized by argon green laser photocoagulation treatment.
CaseNOTHPOs: HP:0030584 (Color vision test abnormality), HP:0007957 (Corneal opacity), HP:0000518 (Cataract)
CaseNOTHPOFreeText: N/A
CasePreviousTesting: N/A
GenotypingMethod: Sanger sequencing of Weber_1994_Family_M_patient_IV-2
PreviouslyPublished: PMID:2000899
SupplementalData: N/A
Variant: The variant is NM_000362.5(TIMP3):c.572A>G, p.Tyr191Cys, which was first referred to in PMID:7894485 as "Tyr168Cys" (due to the removal of a 23-amino acid N-terminal signal peptide from the polypeptide sequence) but encodes Tyr191Cys in the full/updated polypeptide sequence.
ClinVar: 12677
gnomAD: Variant is absent from gnomAD.
VariantEvidence: Variant adds a Cys residue to TIMP3 and is predicted to disrupt tertiary structure.
We performed a trial of retinal gene augmentation in the Pde6a mutant dog using Pde6a delivery by capsid-mutant adeno-associated virus serotype 8, previously shown to have a rapid onset of transgene expression in the canine retina. Subretinal injections were performed in 10 dogs at 29–44 days of age, and electroretinography and vision testing were performed to assess functional outcome. Retinal structure was assessed using color fundus photography, spectral domain optical coherence tomography, and histology. Immunohistochemistry was performed to examine transgene expression and expression of other retinal genes. Treatment resulted in improvement in dim light vision and evidence of rod function on electroretinographic examination. Photoreceptor layer thickness in the treated area was preserved compared with the contralateral control vector treated or uninjected eye. Improved rod and cone photoreceptor survival, rhodopsin localization, cyclic GMP levels and bipolar cell dendrite distribution was observed in treated areas. Some adverse effects including foci of retinal separation, foci of retinal degeneration and rosette formation were identified in both AAV-Pde6a and control vector injected regions.
ExperimentName: Rescue of Pde6a-mutant Cardigan Welsh Corgi dogs with canine Pde6a
RescueModel: Canis lupus familiaris
GeneAlteration: The model harbors a homozygous 1-bp deletion variant at codon 616 that results in a frameshift and a premature stop codon (previously reported in PMID: 10393029 and PMID: 18775863).
RescueVariant: Rescue was performed with wild-type canine Pde6a delivered by AAV8 and expressed under the CMV-chicken beta-actin promoter, in comparison to a GFP control.
RescuePhenotype: HP:0030474 (Undetectable dark-adapted electroretinogram), HP:0000505 (Visual impairment), HP:0007843 (Attenuation of retinal blood vessels), HP:0030610 (Photoreceptor outer segment loss on macular OCT)
RescueMethod: Rescue was performed by subretinal injection of AAV8 particles delivering wild-type canine Pde6a or GFP cDNA (Figures 4, 5, and 6).
RescueEvidence: Rod ERG response shows improvement from undetectable to detectable following AAV-Pde6a injection (Fig. 1). Visual impairment also improved according to visual navigation ability (Fig. 2). Attenuation of retinal blood vessels was prevented as well (Fig. 3). Photoreceptor outer nuclear layer thickness was preserved (Fig. 4). Finally, treatment promoted rod photoreceptor survival (Fig. 5).
ModelVariant: The model does not harbor a variant equivalent to one from the human patients, but rather has a naturally occurring frameshift variant disrupting Pde6a leading to full loss-of-function.
Regulation of melastatin, a TRP-related protein, through interaction with a cytoplasmic isoform
PMID: 11535825
Gene: TRPM1
HGNC: 7146
Disease: congenital stationary night blindness 1C
MONDO: MONDO:0013183
InheritancePattern: autosomal recessive
Prevalence: Congenital stationary night blindness has an estimated prevalence between 1 in 6,000 (PMID: 31427709) and 1 in 300,000 (PMID: 3487908). However, the prevalence of congenital stationary night blindness 1C specifically is unknown.
Penetrance: Penetrance is thought to be complete.
P6 (father of P1, P2, P3) was hemizygous for the mutation c.461del_T (p.Ile154fs) in GPR143/OA1 and is described in the Supplement.
Case#: Paavo_2018_Patient_6, male, 43.1 years of age at time of report, family origin reported as Hispanic
CasePresentingHPOs: N/A
CaseHPOFreeText: The proband has been diagnosed with ocular albinism 1.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: It is not clear whether previous genotyping was performed.
CaseMethod1: Sanger sequencing
CaseMethod2: N/A
CaseGenotypingMethod: The patient's family appears to have been genotyped by Sanger sequencing of the 9 exons from the GPR143 gene.
Variant: The proband harbors the NM_000273.3(GPR143):c.461del (p.Ile154fs) variant in the hemizygous state.
ClinVar: 817370
gnomAD: This variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_000273.3(GPR143):c.461del (p.Ile154fs) is a frameshift variant in exon 4 of 9, and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 62% of the protein product.
CaseAddInfo: The proband has three daughters who carry the variant in the heterozygous state but are reportedly unaffected, other than one daughter reporting difficulty seeing in the dark.
CasePMIDs: N/A
Adult-onset autosomal recessive ataxia associated with neuronal ceroid lipofuscinosis type 5 gene (CLN5) mutations
PMID: 25359263
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
Next-generation sequencing applied to a large French cone and cone-rod dystrophy cohort: mutation spectrum and new genotype-phenotype correlation
PMID: 26103963
Gene: PROM1
HGNC: 9454
Disease: retinitis pigmentosa 41
MONDO: 0012796
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). The proportion of that incidence made up by the specific form caused by biallelic variants in PROM1 is not clear.
Penetrance: Known disease-causing alleles appear to be completely penetrant in the homozygous state, and for at least some heterozygous variants associated with other disease entities.
A 67-year-old male was referred to our clinic for evaluation with a diagnosis of choroideremia. He was diagnosed at the age of 53 after presenting to his ophthalmologist with worsening night and peripheral vision.
Case#: Jauregui_2018_Patient_1, male, 53 years of age at onset, Scottish ancestry
CasePresentingHPOs: HP:0003581 (Adult onset), HP:0000662 (Nyctalopia), HP:0007994 (Peripheral visual field loss), HP:0000533 (Chorioretinal atrophy), HP:0030979 (Dilatation of large choroidal vessels), HP:0007703 (Abnormality of retinal pigmentation), HP:0007663 (Reduced visual acuity), HP:0200070 (Peripheral retinal atrophy), HP:0007722 (Retinal pigment epithelial atrophy), HP:0000518 (Cataract)
CaseHPOFreeText: The patient presented at age 53 with nyctalopia and peripheral visual loss.
CaseNotHPOs: HP:0003593 (Infantile onset), HP:0011463 (Childhood onset)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
CaseMethod1: 31-gene sequencing panel
CaseMethod2: N/A
CaseGenotypingMethod: Variants in CHM and 29 other genes involved in Retinitis pigmentosa or Leber congenital amaurosis were excluded by genotyping panel, which also detected the variant in RPE65.
Variant: The patient harbors the NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant in one allele of RPE65.
ClinVar: 750796
gnomAD: The NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant was not found in gnomAD.
VariantEvidence: Exogenous expression of the variant reveals protein expression levels, cellular localization and retinoid isomerase activity comparable to the wild-type (PMID: 29659842). However, knock-in mouse models exhibit retinyl ester accumulation (PMID: 29659842), abnormally slow regeneration of 11-cis-retinal after light exposure, and ERG results indicative of delayed dark adaptation (PMID: 28041994). Mice with CRISPR-mediated knock-in of the variant also exhibit a splicing defect in RPE65 due to the introduction of a cryptic splice site, which likely triggers a frameshift, exclusion of exons 13 and 14 from the transcript, and premature truncation of the protein product (PMID: 30628748).
CaseAddInfo: The possibility of family consanguinity was not mentioned.
CasePMIDs: N/A
Clinical and genetic investigation of a large Tunisian family with complete achromatopsia: identification of a new nonsense mutation in GNAT2 gene
PMID: 21107338
GeneName: GNAT2
HGNC: 4394
Disease: achromatopsia 4
MonDO ID: MONDO_0013465
Inheritance: autosomal recessive
Clinical features of affected males with X linked ocular albinism
PMID: 8494858
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.
Nyctalopin is essential for synaptic transmission in the cone dominated zebrafish retina
PMID: 17004930
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.
Congenital stationary night blindness in the dog: common mutation in the RPE65 gene indicates founder effect
PMID: 9808841
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
Panel-based whole exome sequencing identifies novel mutations in microphthalmia and anophthalmia patients showing complex Mendelian inheritance patterns
PMID: 29178648
Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test
PMID: 28771251
The interphotoreceptor matrix (IPM) occupies the extracellular space between the apical surface of the retinal pigmented epithelium and the external limiting membrane of the neural retina. This space contains two chondroitin sulfate proteoglycans, designated IPM 150 and IPM 200
Selection B- Gene function is consistent with phenotype.
GOterm: GO:0033165 (interphotoreceptor matrix)
FunctionalEvidence: IMPG1 protein can be purified as a component of an insoluble extracellular layer that is located between apical side of the RPE and the external limiting membrane of the neural retina, known as the interphotoreceptor matrix (Figure 1). This layer is known to support the function and maintenance of photoreceptor cells (PMID: 7344830).
FunctionalHPO: HP:0030612 (Abnormal retinal morphology on macular OCT, specifically photoreceptor outer segment elongation), HP:0007677 (Vitelliform-like macular lesions)
PhenotypeEvidence: The article provides an example of the function of IMPG1 (here referred to as IPM150) as a component of the interphotoreceptor matrix, an insoluble extracellular layer that is located between apical side of the RPE and the external limiting membrane of the neural retina, and which supports the adhesion, function, and maintenance of photoreceptor cells.
Analysis of the involvement of the NR2E3 gene in autosomal recessive retinal dystrophies
PMID: 18294254
Gene: NR2E3
HGNC: 7974
Disease: enhanced S-cone syndrome
MONDO: 0100288
InheritancePattern: autosomal recessive
Prevalence: The overall prevalence of enhanced S cone syndrome is <1 in 1,000,000 (PMID: 30900587).
Penetrance: The penetrance of enhanced S-cone syndrome has been difficult to determine accurately given the rarity of the condition.
LCA was diagnosed in patient 441
Case#: Yzer_2006_Patient_441, female, age 3 months at diagnosis, Belgian maternal and Moroccan paternal origin
CasePresentingHPOs: HP:0003593 (Infantile onset), HP:0000662 (Nyctalopia), HP:0000639 (Nystagmus), HP:0007663 (Reduced visual acuity), HP:0001483 (Eye poking), HP:0000550 (Undetectable electroretinogram)
CaseHPOFreeText: The individual is described as having Leber congenital amaurosis. Age was 15 months at time of last evaluation.
CaseNotHPOs: HP:0000613 (Photophobia), HP:0000563 (Keratoconus), HP:0001098 (Abnormal fundus morphology)
CaseNotHPOFreeText: N/A
CasePreviousTesting: An LCA-specific microarray ChIP was used for initial genotyping, using antisense oligos to screen for 301 known disease-associated variants 6 LCA genes (AIPL1, CRB1, CRX, GUCY2D, RPE65, and RPGRIP1) and two early-onset RP genes (LRAT and MERTK).
CaseMethod1: Sanger sequencing of PCR products from the relevant exon of GUCY2D (or from each of the 20 exons of GUCY2D in the compound heterozygous individual with a novel variant).
CaseMethod2: N/A
CaseGenotypingMethod: The individual was initially screened using an LCA-specific microarray ChIP with antisense oligos to detect 301 known disease-associated variants 6 LCA genes (AIPL1, CRB1, CRX, GUCY2D, RPE65, and RPGRIP1) and two early-onset RP genes (LRAT and MERTK). Subsequent genotyping was performed by Sanger sequencing of PCR products from the relevant exons of the GUCY2D locus.
Variant: The individual is compound heterozygous for the NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) and NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variants.
ClinVar: 9350, 98563
gnomAD: The NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) variant exhibits a maximum allele frequency of 0.000008790 in gnomAD version 2.1.1 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7912849-T-C?dataset=gnomad_r2_1 The NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant exhibits a maximum allele frequency of 0.0002943 in gnomAD version 2.1.1 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7917236-C-T
VariantEvidence: PMID: 9888789 provides evidence supporting the pathogenicity of the NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) variant by showing that the orthologous bovine F514S point mutation severely decreases the intrinsic cyclase activity of the protein and inactivates one of its calcium-responsive activating switches, CRM1. Multiple publications have found functional defects in the NM_000180.4(GUCY2D):c.2302C>T (p.Arg768Trp) variant. PMID: 25477517 shows defective binding to its interacting partner RD3, while PMID: 20050595 and PMID: 23035049 show reduced basal enzymatic activity and inability to interact with the activity-stimulating binding partner GCAP1.
CaseAddInfo: Parents were not reported to be consanguineous. Segregation / phasing of two variants was confirmed by parental genotyping.
CasePMIDs: N/A
Autosomal recessive retinitis pigmentosa caused by mutations in the alpha subunit of rod cGMP phosphodiesterase
PMID: 7493036
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.
TULP3 bridges the IFT-A complex and membrane phosphoinositides to promote trafficking of G protein-coupled receptors into primary cilia
PMID: 20889716
Gene: IFT140
HGNC: 29077
Disease: Short-rib thoracic dysplasia 9 with or without polydactyly
MONDO: 0009964
InheritancePattern: autosomal recessive
Prevalence: Within the lumped disease entity for this curation, the most prevalent form may be retinitis pigmentosa. The prevalence of Saldino-Mainzer syndrome (one of the synonyms of Short-rib thoracic dysplasia 9) is less than 1 in 1,000,000. The prevalence of Leber congenital amaurosis cases caused by IFT140 variants (PMID: 26216056) is calculated to be less than 1 in 3,000,000. Although IFT140 variants are estimated to be responsible for less than 2% of RP, the prevalence of the overall disorder at 1 in 3,000 or 1 in 4,000 means the frequency of these cases could potentially be higher than 1 in 1,000,000.
Penetrance: Known variants for this lumped disease entity appear to be completely penetrant, with highly variable phenotypes and age of onset. On the other hand, the split disease entity caused by monoallelic IFT140 variants appears to have incomplete penetrance.
two missense
Case#: Perrault_2000_Family_9_Proband, male, age unknown, family origin in Algeria with Arab ancestry
CasePresentingHPOs: N/A
CaseHPOFreeText: The individual is described as having Leber congenital amaurosis.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Linkage mapping of the disease locus to chromosome 17p13.1 (PMID: 7581387, PMID: 8641699)
CaseMethod1: Sanger sequencing of PCR products from each of the 20 exons
CaseMethod2: N/A
CaseGenotypingMethod: The individual was included in multi-family homozygosity mapping, establishing linkage to chromosome 17p13.1 and particularly between the D17S1353 and D17S1854 markers (PMID: 7581387, PMID: 8641699). Subsequent genotyping was performed by Sanger sequencing of PCR products from the GUCY2D locus.
Variant: The individual is homozygous for the NM_000180.4(GUCY2D):c.1694T>C (p.Phe565Ser) variant.
ClinVar: 9350
gnomAD: The variant exhibits a maximum allele frequency of 0.000008790 in gnomAD version 2.1.1 (in the European non-Finnish population, with no homozygotes). https://gnomad.broadinstitute.org/variant/17-7912849-T-C?dataset=gnomad_r2_1
VariantEvidence: The evidence supporting the pathogenicity of the variant is limited to computational prediction alone.
CaseAddInfo: The family is reportedly consanguineous.
CasePMIDs: PMID: 7581387, PMID: 8641699
Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor
PMID: 11956231
Gene: LRP5
HGNC: 6697
Disease: osteoporosis-pseudoglioma syndrome
MONDO: 0009820
InheritancePattern: autosomal recessive
Prevalence: osteoporosis-pseudoglioma syndrome is estimated to occur in 1 out of every 2,000,000 live births.
Penetrance: The penetrance of the phenotype among homozygous or compound heterozygous cases appears to be complete, while heterozygous carriers of deleterious variants appear to be mildly affected.
Disease mechanisms of X‐linked cone dystrophy caused by missense mutations in the red and green cone opsins
PMID: 34547123
Gene: OPN1LW
HGNC: 9936
Disease: protan color blindness
MONDO: 0010565
InheritancePattern: X-linked
Prevalence: The overall prevalence of protan color blindness is approximately 1% in males, which is higher than that of blue cone monochromacy (~1 in 100,000, PMID: 35759666).
Penetrance: Known disease-causing alleles appear to be almost completely penetrant in males (PMID: 21167193).
In the affected individuals of three Flemish families with the complete form of CSNB a novel NYX mutation, c.855delG was identified. This deletion is predicted to lead to a frameshift mutation, p.Asp286ThrfsX62 causing a premature stop codon.
Case#: Leroy_2009_Family_A_Patient_III-14, male, age 58 years, family of Flemish ethnicity and Belgian national origin
CasePresentingHPOs: HP:0030640 (Complete congenital stationary night blindness), HP:0007663 (Reduced visual acuity), HP:0007984 (Electronegative electroretinogram), HP:0000639 (Nystagmus), HP:0003593 (Infantile onset), HP:0025404 (Abnormal visual fixation), HP:0000545 (Myopia), HP:0001104 (Macular hypoplasia), HP:0001417 (X-linked inheritance)
CaseHPOFreeText: N/A
CaseNotHPOs: HP:0000613 (Photophobia), HP:0030526 (Severe constriction of peripheral visual field), HP:0030602 (Abnormal fundus autofluorescence imaging), HP:0025158 (Hyperautofluorescent retinal lesion)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
CaseMethod1: Sanger sequencing of PCR amplified exons from NYX
CaseMethod2: Haplotype analysis using microsatellite markers surrounding the NYX locus, in multiple apparently unrelated patients sharing the same variant
CaseGenotypingMethod: The proband and family members were subjected to Sanger sequencing of NYX to identify the variant, followed by haplotype analysis in comparison to apparently unrelated patients harboring the same variant.
Variant: The proband harbors the NM_022567.2:c.856del (p.Asp286ThrfsTer62) variant on the X chromosome.
CAID: CA2573050962
gnomAD: NM_022567.2:c.856del (p.Asp286ThrfsTer62) was not found in gnomAD.
VariantEvidence: The NM_022567.2:c.856del (p.Asp286ThrfsTer62) variant is located in exon 2/2 and is not predicted to trigger NMD. It is predicted to introduce a premature stop codon that would disrupt the C-terminal 41% of the protein product while adding 62 different amino acids.
CaseAddInfo: The proband comes from a large family with inheritance through an unaffected carrier mother and transmission to a grandson through an unaffected carrier daughter. This variant appears in 3 different families of Flemish Belgian origin, and is suspected to be a founder mutation in this population.
CasePMIDs: N/A
A second IMPG1 mutation, c.807 + 5G > A, was found in patient #2 of the consanguineous Turkish family 11-151 in a homozygous state (Table 1). Homozygosity was confirmed by segregation analysis in the genomic DNA of the parents. The intronic c.807 + 5G > A nucleotide substitution resides within in the conserved 5’ splice site of exon 7 and is predicted to weaken the donor splice site by 20%. The analysis of cDNA derived from HEK293 cells transfected with a construct containing the c.807 + 5G > A mutation, revealed aberrant pre-mRNA splicing; exon 7 was skipped in about half of the transcripts leading to a 194 bp as well as the 335 bp reverse transcription (RT)-PCR product amplified in controls (Figure 1). An additional faint band of ~270 bp of unknown origin was seen in cells transfected with the mutant construct. The in vitro splice assay thus confirms the bioinformatic prediction of missplicing due to the c.807 + 5G > A variant that likely leads to nonsense-mediated mRNA decay (NMD) of the aberrant mRNA.
Case#: Brandl_2017_Family_11-151_Proband_#2, male, age 10 years at time of report, national origin reported as Turkish
CasePresentingHPOs: HP:0007677 (Vitelliform-like macular lesions), HP:0007663 (Reduced visual acuity, 0.2 logMAR), HP:0000493 (Abnormal foveal morphology, specifically bilateral central foveal detachment of neurosensory retina), HP:0008179 (Decreased Arden ratio of electrooculogram), HP:0030612 (Abnormal retinal morphology on macular OCT)
CaseHPOFreeText: The patient has been diagnosed with vitelliform macular dystrophy with onset in early childhood. The abnormal foveal morphology refers specifically to foveal detachment. Photoreceptor outer segments were elongated.
CaseNotHPOs: HP:0000512 (Abnormal electroretinogram)
CaseNotHPOFreeText: RPE and Bruch's membrane appeared normal.
CasePreviousTesting: Previous testing appears to have been limited to Sanger sequencing of the BEST1 and PRPH2 loci.
CaseMethod1: Sanger sequencing of the exons and flanking intronic sequences of IMPG1 and IMPG2.
CaseMethod2: N/A
CaseGenotypingMethod: Previous testing appears to have been limited to Sanger sequencing of the BEST1 and PRPH2 loci, while subsequent genotyping included Sanger sequencing of the exons and flanking intronic sequences of IMPG1 and IMPG2.
Variant: The proband harbors the NM_001563.4(IMPG1):c.807+5G>A variant in the homozygous state.
ClinVar: 1240016
gnomAD: The NM_001563.4(IMPG1):c.807+5G>A variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_001563.4(IMPG1):c.807+5G>A is an intron 7 variant that has mini-gene assay evidence from this article (Figure 1) confirming a partial deleterious impact on the splicing of the transcript. The variant triggers skipping of exon 7 in approximately half of the transcripts. This partial defect appears to lead to in-frame loss of 141 bp (47 amino acids) corresponding to ~6% of the protein product.
CaseAddInfo: The parents of the proband are consanguineous and are clinically asymptomatic at ages 35 and 40 years, respectively.
CasePMIDs: N/A
c.333_360+14del42insCTT
Case#: Zou_2017_Patient_F1-II:1, male, age 4 at time of report, family national origin reported to be from China
CasePresentingHPOs: HP:0000639 (Nystagmus), HP:0000613 (Photophobia), HP:0007663 (Reduced visual acuity), HP:0007750 (Hypoplasia of the fovea), HP:0007894 (Hypopigmentation of the fundus)
CaseHPOFreeText: The proband has been diagnosed with ocular albinism 1. Foveal hypoplasia was described as severe. Best-corrected visual acuity was limited to light perception.
CaseNotHPOs: HP:0007730 (Iris hypopigmentation)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
CaseMethod1: Sanger sequencing
CaseMethod2: N/A
CaseGenotypingMethod: Patients were genotyped by Sanger sequencing of PCR products from the 9 exons of the GPR143 gene.
Variant: The proband harbors the NM_000273.3(GPR143):c.333_360+14delinsCTT variant in the hemizygous state.
CAID: CA2573320702
gnomAD: This variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_000273.3(GPR143):c.333_360+14delinsCTT is an indel variant removing the 3' end of exon 2 including the canonical splice donor site, and is predicted to either introduce a premature stop codon or exon skipping.
CaseAddInfo: N/A
CasePMIDs: N/A
A Novel GUCY2D Mutation, V933A, Causes Central Areolar Choroidal Dystrophy
PMID: 22695961
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.
The disintegrin domain of MDC-9 lacks an RGD motif but has recently been reported to bind the alpha(6)beta(1) integrin; however, it is unclear whether MDC-9 can bind other integrins. In the present study myeloma cells, but not lymphoblastoid cells, were shown to bind to immobilised, recombinantly expressed MDC-9 disintegrin domain (A9dis). Binding was divalent cation-dependent, being supported by Mn(2+) and Ca(2+). Adhesion of myeloma cells to A9dis was completely inhibited by an antibody to the alpha(v)beta(5) integrin but not by antibodies to other subunits. RGD-containing peptides had no effect on binding, suggesting that MDC-9 interacts with alpha(v)beta(5) in an RGD-independent manner. Flow cytometric analyses demonstrated that myeloma cells, but not lymphoblastoid cells, expressed alpha(v)beta(5) on the cell membrane. These data indicated that the disintegrin domain of MDC-9 can function as an adhesion molecule by interacting with an alpha(v)beta(5) integrin.
Selection B- Gene function is consistent with phenotype.
Title: ADAM9 (MDC-9) functions as an adhesion molecule by interacting with integrins.
GOterm: GO:0033630 (positive regulation of cell adhesion mediated by integrin)
FunctionalEvidence: Melanoma cells bind to they the immobilized recombinant ADAM9 disintegrin domain in a manner that is dependent on divalent cations (Mn2+ or Ca2+). The interaction can also be disrupted by an antibody to the alpha(v)beta(5) integrin, indicating that the cell-cell adhesion function of ADAM9 is mediated by an interaction with this molecule.
FunctionalHPO: HP:0000546 (Retinal degeneration), HP:0007703 (Abnormality of retinal pigmentation), HP:0030610 (Photoreceptor outer segment loss on macular OCT
PhenotypeEvidence: This evidence is consistent with evidence that Adam9 knockout mice exhibit a gap between the photoreceptor outer nuclear segment and the retinal pigment epithelium, indicating that loss of this adhesion molecule may impair the integrity of retinal organization.
Clinical and Molecular Landscape of GLRA2 in X-Linked Early-Onset High Myopia
PMID: 40227176
Gene: OPN1LW
HGNC: 9936
Disease: protan color blindness
MONDO: 0010565
InheritancePattern: X-linked
Prevalence: The overall prevalence of protan color blindness is approximately 1% in males, which is higher than that of blue cone monochromacy (~1 in 100,000, PMID: 35759666).
Penetrance: Known disease-causing alleles appear to be almost completely penetrant in males (PMID: 21167193).
mutation
Case#: Meins_1993_Proband, male, age 58 years at time of report, national origin reported as German
CasePresentingHPOs: Nyctalopia HP:0000662, Reduced visual acuity HP:0007663, Peripheral visual field loss HP:0007994, Central scotoma HP:0000603, Decreased light- and dark-adapted electroretinogram amplitude HP:0000654, Decreased Arden ratio of electrooculogram HP:0008179, Bone spicule pigmentation of the retina HP:0007737, Macular flecks HP:0011507
CaseHPOFreeText: The proband has been diagnosed with retinitis pigmentosa, following a previous diagnosis of Stargardt's macular dystrophy almost 1 decade earlier. First onset of night vision loss was reportedly in his teens.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous testing in the proband is not described but genotyping appears to have been limited to the PRPH2 locus and did not include other candidate genes.
CaseMethod1: single-strand conformational polymorphism (SSCP) analysis of PCR products from the 3 exons of PRPH2
CaseMethod2: Sanger sequencing of PRPH2
CaseGenotypingMethod: Previous testing in the proband is not described but genotyping appears to have been limited to the PRPH2 locus and did not include other candidate genes. Genotyping was performed by SSCP analysis of PCR products from the 3 exons of PRPH2 and Sanger sequencing of PRPH2.
Variant: The proband harbors the NM_000322.5(PRPH2):c.136C>T (p.Arg46Ter) variant in the heterozygous state.
ClinVar ID: 13179
gnomAD: The NM_000322.5(PRPH2):c.136C>T (p.Arg46Ter) variant is found in gnomAD v4.0.0 at a frequency of 0.00004005 (3 alleles / 74906 total alleles, with 0 homozygotes) in the African / African-American population https://gnomad.broadinstitute.org/variant/6-42722199-G-A?dataset=gnomad_r4
VariantEvidence: NM_000322.5(PRPH2):c.136C>T (p.Arg46Ter) is a nonsense variant in exon 1 of 3 that is predicted to trigger nonsense-mediated decay or at least to truncate the C-terminal 87% of the protein product.
CaseAddInfo: The proband has a similarly affected father and grandfather who have not been genotyped.
CasePMIDs: N/A
c.C1870T (p.R624W)
Case#: Zhang_2016_Pedigree_C_Proband_C001, male, 32 years old at time of report, national origin reported to be Indian.
CasePresentingHPOs: HP:0007770 (Hypoplasia of the retina), HP:0007685 (Peripheral retinal avascularization), HP:0030666 (Retinal neovascularization)
CaseHPOFreeText: The proband has been diagnosed with familial exudative vitreoretinopathy (FEVR).
CaseNotHPOs: N/A
CaseNotHPOFreeText: Premature birth, maternal drug intake during pregnancy, or other ocular disease associated with osteopenia / osteoporosis
CasePreviousTesting: Whole exome sequencing was performed, ruling out variations in the NDP, FZD4, TSPAN12, and ZNF408 loci.
CaseMethod1: Whole exome sequencing
CaseMethod2: Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 locus
CaseGenotypingMethod: Whole exome sequencing was performed, ruling out variations in the NDP, FZD4, TSPAN12, and ZNF408 loci. This was followed by Sanger sequencing of PCR-amplified exons and flanking regions of the LRP5 locus.
Variant: The patient harbors the NM_002335.4(LRP5):c.1870C>T (p.Arg624Trp) variant in the homozygous state.
ClinVar: 1477058
gnomAD: The NM_002335.4(LRP5):c.1870C>T (p.Arg624Trp) variant was found in gnomAD v2.1.1 at a maximum allele frequency of 0.000008796 (1/113688) in the European non-Finnish population https://gnomad.broadinstitute.org/variant/11-68174060-C-T
VariantEvidence: NM_002335.4(LRP5):c.1870C>T (p.Arg624Trp) is a missense variant in exon 9 out of 23 that has evidence of a functional impact on the protein product. The variant was expressed in STF cells harboring a luciferase reporter construct, showing a reduced (hypomorphic) ability to induce luciferase reporter activity compared with wild-type control LRP5. (Figure 3).
CaseAddInfo: The proband shares the homozygous genotype with his affected mother, although the father's genotype is not available. The asymptomatic uncle and aunt are heterozygous.
CasePMIDs: N/A
missense
Case#: Meindl_1996_Family_F47_Proband, male, age not specified, family origin either German or British
CasePresentingHPOs: HP:0000510 (Rod-cone dystrophy)
CaseHPOFreeText: The proband and affected family members have been diagnosed with retinitis pigmentosa, with an X-linked pattern of inheritance. 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.294C>A (p.His98Gln) variant in the hemizygous state.
ClinVar: 98775
gnomAD: The variant was not found in gnomAD v.2.1.1.
VariantEvidence: NM_001034853.2(RPGR):c.294C>A (p.His98Gln) is a missense variant and does not have associated evidence of impact on RPGR function.
CaseAddInfo: The proband is a member of Family 47.
CasePMIDs: N/A
patients 2.1
Case#: Hull_2016_Patient_2.1, female, 45 years of age at onset, Irish ancestry
CasePresentingHPOs: HP:0003581 (Adult onset), HP:0007663 (Reduced visual acuity), HP:0001141 (Severely reduced visual acuity), HP:0200065 (Chorioretinal degeneration), HP:0000580 (Pigmentary retinopathy), HP:0030474 (Undetectable dark-adapted electroretinogram), HP:0008275 (Abnormal light-adapted electroretinogram)
CaseHPOFreeText: The patient presented at age 45 with central visual disturbance. Anterior retina was well-preserved.
CaseNotHPOs: HP:0003593 (Infantile onset), HP:0011463 (Childhood onset)
CaseNotHPOFreeText: N/A
CasePreviousTesting: Variants in REP1 and PRPH2 were initially excluded.
CaseMethod1: Candidate gene sequencing
CaseMethod2: Bidirectional, targeted Sanger sequencing within the RPE65 locus
CaseGenotypingMethod: Bidirectional Sanger sequencing of exon 13 of the RPE65 gene and flanking sequences
Variant: The patient harbors the NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant in one allele of RPE65.
ClinVar: 750796
gnomAD: The NM_000329.3(RPE65):c.1430A>G (p.Asp477Gly) variant was not found in gnomAD.
VariantEvidence: Exogenous expression of the variant reveals protein expression levels, cellular localization and retinoid isomerase activity comparable to the wild-type (PMID: 29659842). However, knock-in mouse models exhibit retinyl ester accumulation (PMID: 29659842), abnormally slow regeneration of 11-cis-retinal after light exposure, and ERG results indicative of delayed dark adaptation (PMID: 28041994). Mice with CRISPR-mediated knock-in of the variant also exhibit a splicing defect in RPE65 due to the introduction of a cryptic splice site, which likely triggers a frameshift, exclusion of exons 13 and 14 from the transcript, and premature truncation of the protein product (PMID: 30628748).
CaseAddInfo: The possibility of family consanguinity was not mentioned.
CasePMIDs: N/A
Kinetics of visual pigment regeneration in excised mouse eyes and in mice with a targeted disruption of the gene encoding interphotoreceptor retinoid-binding protein or arrestin
PMID: 10508404
Gene: RBP3
HGNC: 9921
Disease: retinitis pigmentosa 66
MONDO: 0014093
InheritancePattern: autosomal recessive
Prevalence: RBP3-related cases are believed to be very rare (possibly with estimated prevalence of less than 1 in 1,000,000), however, it is believed that there may be under-diagnosis (PMID: 37806543).
Penetrance: RBP3 disease-causing variants appear to have complete penetrance.
one case
Case#: Pineda-Trujillo_Patient_NCL-22, male, age 9 at onset and age 14 at death, Colombian origin with family ethnicity reported as an admixture of Spanish, Native American, and African ancestry
CasePresentingHPOs: HP:0003208 (Fingerprint intracellular accumulation of autofluorescent lipopigment storage material), HP:0003621 (Juvenile onset), HP:0000572 (Visual loss), HP:0003678 (Rapidly progressive), HP:0011421 (Death in adolescence), HP:0025406 (Asthenia), HP:0200085 (Limb tremor), HP:0000618 (Blindness), HP:0002540 (Inability to walk), HP:0000708 (Behavioral abnormality), HP:0007064 (Progressive language deterioration), HP:0001336 (Myoclonus), HP:0001250 (Seizure), HP:0002120 (Cerebral cortical atrophy), HP:0001272 (Cerebellar atrophy), HP:0002392 (EEG with polyspike wave complexes)
CaseHPOFreeText: Onset was at age 9, with the first presenting phenotype being visual failure rather than mental retardation. Electron microscopy of skin biopsies found inclusions consisting of fingerprint profiles, which were often condensed and sometimes associated with lipid droplets. Tremor was observed in lower limbs. Blindness and inability to walk developed at approximately age 10 (within a year of symptom onset). Behavioral changes, gradual loss of language, myoclonus, and seizures all occurred within months of onset. Seizures were poorly responsive to valproate or clonazepam. Generalized cortical and cerebellar atrophy without signal intensity changes were seen by NMR at CT scans at age 12. EEG specifically showed a generalized pattern of high-voltage polyspike–slow waves. Patient died at age 14.
CaseNotHPOs: HP:0003205 (Curvilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0003226 (Rectilinear intracellular accumulation of autofluorescent lipopigment storage material), HP:0001922 (Vacuolated lymphocytes), HP:0003457 (EMG abnormality), HP:0100285 (EMG: impaired neuromuscular transmission)
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous testing relied on clinical testing to establish neuronal ceroid lipofuscinosis (CLN), then used 10 different microsatellite markers to evaluate the 6 loci known at the time to be associated with CLN. (Note: This list of CLN-associated loci has since expanded from 6 to 8-12 genes.) The pedigree indicates consistent segregation of the disease phenotype with biallelic inheritance of the three markers in the CLN5 locus. CLN genes were then PCR-amplified and subjected to Sanger sequencing, identifying a variant in CLN5. Genome-wide analysis methods were not used.
CaseMethod1: Linkage analysis with 10 microsatellite markers across 6 candidate loci known to be associated with CLN phenotypes.
CaseMethod2: CLN genes (specifically CLN3 and CLN5) were PCR-amplified and subjected to Sanger sequencing, identifying a variant in CLN5.
CaseGenotypingMethod: CLN5 PCR products were subjected to PshAI endonuclease digestion, as the variant abolishes a restriction site. Genome-wide analysis methods were not used.
Variant: Patient was homozygous for NM_006493.4(CLN5):c.188G>A (p.Arg63His), (although this variant is referred to in the article as c.1627G>A or p.Arg112His).
ClinVar: 2567
gnomAD: The variant is reported to have a maximum allele frequency of 0.00003274 (in the South Asian population, with no homozygous individuals). https://gnomad.broadinstitute.org/variant/13-77569212-G-A
VariantEvidence: The variant encodes a missense substitution, and exhibits defective localization to the ER rather than the lysosome (PMID:20052765).
CaseAddInfo: N/A
CasePMIDs: N/A
The Role of Ceroid Lipofuscinosis Neuronal Protein 5 (CLN5) in Endosomal Sorting
PMID: 22431521
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
A knockin mouse model of the Bardet–Biedl syndrome 1 M390R mutation has cilia defects, ventriculomegaly, retinopathy, and obesity
PMID: 18032602
Gene: BBS1
HGNC: 966
Disease: Bardet-Biedl syndrome 1
MONDO: 0008854
InheritancePattern: autosomal recessive
Prevalence: The prevalence of BBS1 variants among Bardet-Biedl syndrome cohorts has been reported as at least 20% (PMID: 19402160), while the prevalence of Bardet-Biedl syndrome overall has been estimated between 1 in 13,500 and 1 in 160,000 live births, depending on the population (PMID: 22713813).
Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete.
Linkage analysis established complete segregation of the BCAMD phenotype (maximum multipoint LOD score, 3.8) with DNA markers at chromosome 6, region p12.3-q16. Recombination events defined a critical interval spanning 30.7 cM at the long arm of chromosome 6 between markers D6S269 and D6S300. This interval encompasses several retinal dystrophy loci, including the ELOVL4 gene, mutated in autosomal dominant Stargardt disease, and the RIM1 gene, mutated in autosomal dominant cone-rod dystrophy, as well as the retinally expressed GABRR1 and -2 genes. Mutation screening of these four genes revealed no mutations. Sequence analysis of the interphotoreceptor matrix proteoglycan 1 gene IMPG1, also residing in the BCAMD locus, revealed a single base-pair change (T-->C) of nucleotide 1866 in exon 13, resulting in a Leu579Pro amino acid substitution
FamilyLabel: van_Lith-Verhoeven_2004_Family
Family#PresentingHPOs: HP:0007754 (Macular dystrophy), HP:0007769 (Peripheral retinal degeneration), HP:0032037 (Mildly reduced visual acuity, progressive), HP:0008179 (Decreased Arden ratio of electrooculogram)
FamilyPresentingHPOFreeText: The affected family members have been diagnosed with benign concentric annular macular dystrophy (BCAMD), segregating with an autosomal dominant mode of inheritance. Visual acuity was initially normal but progressed to phenotype similar to retinitis pigmentosa, including peripheral retinal involvement and photoreceptor cell dysfunction (shown by ERG).
FamilyNotHPOs: HP:0000613 (Photophobia), HP:0000551 (severe Color vision defect)
FamilyNotHPOFreeText: N/A
CountryOrigin: The family is reportedly Dutch.
Ethnicity: Not specifically described
Race: N/A
Family#PreviousTesting: Linkage analysis was performed using a combination of a whole genome scan and microsatellite markers within candidate retinal loci.
Family#Method1: Genome-wide and candidate-focused linkage analyses
Family#Method2: Sanger sequencing of the candidate genes ELOVL4, GABR1, GABR2 and IMPG1
Family#GenotypingMethod: Linkage analysis was performed using a genome-wide scan as well as microsatellite markers from candidate loci. Sanger sequencing then analyzed the candidate retina genes from the linkage region; ELOVL4, GABR1, GABR2 and IMPG1
Affected: 11 genotyped
Unaffected: 5 genotyped
Segregations: 10 segregations are shown by the pedigree in Figure 1.
PublishedLOD: 3.8
eLOD: N/A
AddSegregationInfo: N/A
ProbandLabel: van_Lith-Verhoeven_2004_Family_Proband_II-4
Variant: The affected family members harbor the NM_001563.4(IMPG1):c.1736T>C (p.Leu579Pro) variant in the heterozygous state.
ClinVar: 1008228
gnomAD: This variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_001563.4(IMPG1):c.1736T>C (p.Leu579Pro) is a missense variant that does not have evidence confirming an impact on the gene product.
FamilyAddInfo: The family's national origin has been reported as Dutch.
FamilyPMIDs: N/A
Arg124End (CGA to TGA)
Case#: Morimura_1998_Family_9190_Patient_II-1, female, age and family origin not specified
CasePresentingHPOs: HP:0000546 (Retinal degeneration)
CaseHPOFreeText: While specific phenotypes are not provided, the initial diagnosis of Leber congenital amaurosis indicates that the proband was either born blind or lost vision within a period of months after birth.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: All 14 RPE65 exons and flanking sequences were PCR-amplified and subjected to single-strand conformation polymorphism analysis (SSCA).
CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA
CaseMethod2: Sanger sequencing of all 14 exons of RPE65
CaseGenotypingMethod: PCR-amplified exons identified by SSCA as candidates to harbor variants were subjected to Sanger sequencing.
Variant: The proband is a compound heterozygote within the RPE65 locus, harboring the NM_000329.3(RPE65):c.370C>T (p.Arg124Ter) and NM_000329.3(RPE65):c.962dup (p.Asn321fs) variants.
ClinVar: 98866, 98902
gnomAD: The NM_000329.3(RPE65):c.370C>T (p.Arg124Ter) variant has a maximum allele frequency of 0.0003676 (within the African / African-American population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68910339-G-A The NM_000329.3(RPE65):c.962dup (p.Asn321fs) variant has a maximum allele frequency of 0.0001148 (within the African / African-American population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68904660-A-AT
VariantEvidence: NM_000329.3(RPE65):c.370C>T (p.Arg124Ter) is a paternal nonsense variant predicted to either trigger NMD or truncate 77% of the protein product. NM_000329.3(RPE65):c.962dup (p.Asn321fs) is a maternal frameshift variant predicted to either trigger NMD or truncate 40% of the protein product.
CaseAddInfo: Genotyping of the proband's parents revealed that the variants are in trans. The possibility of parental consanguinity was not mentioned.
CasePMIDs: N/A
the affected individual in family E070 originally was classified as being an isolate case of RP. In view of her being a compound heterozygote with two missense mutations, she was recategorized as having recessive RP.
Case#: Morimura_1998_Family_E070_Patient_III-4, female, age and family origin not specified
CasePresentingHPOs: HP:0000546 (Retinal degeneration)
CaseHPOFreeText: While specific phenotypes are not provided, the initial diagnosis of isolate retinitis pigmentosa (later recategorized to recessive retinitis pigmentosa) indicates that the proband maintained central vision during the first decade of life and subsequently experienced severe vision loss.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: All 14 RPE65 exons and flanking sequences were PCR-amplified and subjected to single-strand conformation polymorphism analysis (SSCA).
CaseMethod1: Screening of PCR-amplified RPE65 exons using SSCA
CaseMethod2: Sanger sequencing of all 14 exons of RPE65
CaseGenotypingMethod: PCR-amplified exons identified by SSCA as candidates to harbor variants were subjected to Sanger sequencing.
Variant: The proband is a compound heterozygote harboring the NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) and NM_000329.3(RPE65):c.1355T>G (p.Val452Gly) variants.
ClinVar: 13115, 13116
gnomAD: The NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) variant has a maximum allele frequency of 0.0002406 (in the African / African-American population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68910541-G-A The NM_000329.3(RPE65):c.1355T>G (p.Val452Gly) variant has a maximum allele frequency of 0.00005660 (in the Latino / Admixed American population, with no homozygotes): https://gnomad.broadinstitute.org/variant/1-68896843-A-C
VariantEvidence: The NM_000329.3(RPE65):c.271C>T (p.Arg91Trp) missense variant was also found in apparently unrelated patients diagnosed with Leber congenital amaurosis (Figure 2B). A separate publication (PMID: 16754667) expressed this missense variant in non-patient cells and showed that it abolished the isomerohydrolase activity of the protein product, reduced its stability, and shifted the subcellular localization from predominantly membrane-associated to predominantly cytosolic. The NM_000329.3(RPE65):c.1355T>G (p.Val452Gly) variant is a missense mutation without evidence of gene impact.
CaseAddInfo: The two variants are strongly suspected to be in trans, but one parent was not genotyped. A heterozygous carrier of the NM_000329.3(RPE65):c.1355T>G (p.Val452Gly) variant was found to be unaffected. Potential consanguinity between the parents was not reported.
CasePMIDs: N/A
The mutant protein was shown to dimerize in culture cells and retain its MMP inhibitory activity.
NonPatientCell: ARPE-19 (human retinal pigment epithelial) cell line (CLO:0001749, CL:0009004)
GeneFunction: GO:0008191 (metalloendopeptidase inhibitor activity), GO:0046872 (metal ion binding), GO:0002020 (protease binding), GO:0005615 (active in extracellular space), GO:0031012 (active in extracellular matrix)
GeneAlteration: A TIMP3 expression construct encoding the Glu162Lys variant (referred to in the paper as "Glu139Lys") was generated by PCR-based mutagenesis of the wild-type pCDNA3-TIMP3.
FunctionalEvidence: The TIMP3 variant was exogenously expressed in ARPE-19 cells alongside a mock transfected control (not a wild-type control). Immunoblotting of non-reduced samples detected both monomeric (24 kDa) and dimeric (48 kDa) forms of the variant (Figure 8). Reverse zymographs of extracellular matrix from both wild-type TIMP3- and variant TIMP3-transfected cells revealed the presence of the dimeric species for the variant but not the wild-type, and confirmed its intact metalloproteinase inhibitory activity (Figure 9). This indicated that the free cysteine present in the variant may not have compromised metalloproteinase inhibitory activity, but likely facilitated an intramolecular disfulfide bonding interaction with another TIMP3 molecule. This gain-of-function interpretation of the variant effect would be consistent with the autosomal dominant mechanism of inheritance.
FAVariants: Variant used was NM_000362.5(TIMP3):c.484G>A (p.Glu162Lys) (CAID:CA411540222). The variant is referred to in this publication as "Glu139Lys" (due to the removal of a 23-amino acid N-terminal signal peptide from the polypeptide sequence) but encodes Glu162Lys in the full/updated polypeptide sequence.
Identification of a novel mutation in the human PDE6A gene in autosomal recessive retinitis pigmentosa: homology with the nmf28/nmf28 mice model
PMID: 21039428
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.