C560Rβ3 caused platelet integrin αIIbβ3 to Bind Fibrinogen Continuously yet Resulted in a Severe Bleeding Syndrome and Increased Murine Mortality
PMID: 23551977
Gene: ITGA2B and ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: This article talks about a GT variant however in mice, not humans.
Integrins on Rat Osteoclasts: Characterization of Two Monoclonal Antibodies (F4 and F11) to Rat p3
PMID: 1585837
Gene: ITGA2B and ITGB3
HGNC: 6138 and 6156
NoEvidence: This article does not mention Glanzmann thrombasthenia probands with variants in ITGA2B and/or ITGB3; therefore, there is no evidence
Effectsofanovellowvolumeresuscitationsolutionsoncoagulationandplateletfunction
PMID: 31042735
Gene: ITGA2B and ITGB3
HGNC 6138 and 6156
NoEvidence: This article does not mention Glanzmann thrombasthenia case reports/probands and variants in ITGA2B and/or ITGB3 are not mentioned.
Mutations in theb3 gene giving rise to type IGlanzmann thrombasthenia in twofamilies in Portugal
PMID: 14985172
Gene: ITGB3
HGNC: 6156
Genetic analysis of integrin function in man:LAD-1 and other syndromes
PMID: 10936446
Gene: ITGB3
HGNC: 6156
InsufficientEvidence: This article mentions variants in the ITGB3 gene; however, the variants are not connected to GT probands; therefore, we have insufficient evidence
A novel (288delC) mutation in exon 2 of GPIIb associated with type I Glanzmann's thrombasthenia
PMID: 11091187
Gene: ITGA2B and/or ITGB3
HGNC: 6138 and 6156
Secondary prophylaxis with warfarin for recurrent thrombosis in a patient with Glanzmann thrombasthenia and F5 G1691A
PMID: 21848888
Gene: ITGA2B and/or ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: This article mentions a Glanzmann thrombasthenia patient; however, no variants in ITGA2B and/or ITGB3 are mentioned
Glanzmann thrombasthenia
PMID: 16722529
Gene: ITGA2B and/or ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: This article mentions many variants in ITGA2B/ITGB3 (See Fig. 1 and 2); however, no mention of probands with these variants
A novel ELISA for diagnosis of Glanzmann’s thrombasthenia and the heterozygote carriers
PMID: 22183252
Gene: ITGA2B and ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: This article mentions variants in 10 GT patients; however, it does not specify each case/proband with their gender/age/ethnicity and bleeding phenotypes.
Missed at first Glanz: Glanzmann thrombasthenia initially misdiagnosed as Von Willebrand Disease
PMID: 30551951
Gene: ITGA2B and/or ITGB3 (Patient has GT; therefore, these genes may be involved)
HGNC: 6138 and 6156
InsufficientEvidence: Proband is presented in this article with GT; however, no variant information is provided therefore insufficient evidence
Autoimmune Thrombocytopenic Purpura (AITP) andAcquired Thrombasthenia Due to Autoantibodies to GPIIb-IIIa in a Patient With an Unusual Platelet MembraneGlycoprotein Composition
PMID: 9462551
Gene: ITGA2B and ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: This article mentions a case report of a patient with thrombocytopenia; however, there is no mention of this proband harboring variants in ITGA2B and/or ITGB3
The use of recombinant factor VIIa in a patient with severe Glanzmann's thrombasthenia to facilitate insertion of a Port-a-Cath.
PMID: 10695773
Gene: ITGA2B and/or ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: This article mentions a proband with GT; however, no variants in ITGA2B and/or ITGB3 were mentioned in this individual therefore there is insufficient evidence
Note: Able to get PDF of article; however, was not able to use Hypothes.is on the PDF
A new multiplex PCR and conformation‐sensitive gel electrophoresis strategy for mutation detection in the platelet glycoprotein αIIb and β3 genes
PMID: 17083650
Gene: ITGA2B and/or ITGB3
HGNC: 6138 and 6156
Two Human Antibodies Reacting With Different Epitopes on Integrin Beta 3 of Platelets and Endothelial Cells
PMID: 7517865
Gene: ITGA2B and/or ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: This mentions a Glanzmann thrombasthenia patient (case report); however, no variants in ITGA2B and/or ITGB3 are mentioned in this patient; therefore, we have insufficient evidence
Novel and Recurrent Mutations ofITGA2BandITGB3Genes inKorean Patients with Glanzmann Thrombasthenia
PMID: 22190468
Gene: ITGA2B and ITGB3
HGNC: 6138 and 6156
Severe Juvenile Vaginal Bleeding Due to Glanzmann's Thrombasthenia: Case Report and Review of the Literature
PMID: 9495374
Gene: ITGA2B and/or ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: This mentions a Glanzmann thrombasthenia patient; however, no variants in ITGA2B and/or ITGB3 are mentioned in this patient; therefore, we have insufficient evidence
Fetal-neonatal alloimmune thrombocytopenia and unexpected Glanzmann thrombasthenia carrier: report of two cases
PMID: 15819676
Gene: ITGA2B and ITGB3
HGNC: 6138 and 6156
Nonsense Mutation in Exon-19 of GPIIb Associatedwith Thrombasthenic Phenotype.Failure of GPIIb(597-1008) to Form Stable Complexeswith GPIIIa
PMID: 12008952
Gene: ITGA2B
HGNC: 6138
Sustained engraftment and resolution of bleeding phenotype after unrelated cord blood hematopoietic stem cell transplantation for severe glanzmann thrombasthenia.
PMID: 19648793
Genes: ITGA2B and/or ITBG3
HGNC: 6138 and 6156
InsufficientEvidence: This article mentions an individual with GT; however, there is no mention of variants in ITGA2B and/or ITGB3 therefore we have insufficient evidence
The effect of platelets on fibrin gel structure formed in the presence of recombinant factor VIIa in hemophilia plasma and in plasma from a patient with Glanzmann thrombasthenia
PMID: 15670032
Gene: ITGA2B and/or ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: This article mentions a patient with GT; however, the patient does not have variants in ITGA2B and/or ITGB3
Further Characterization of the Thrombasthenia-related Idiotype OG. Antiidiotype Defines a Novel Epitope(s) Shared by Fibrinogen BE Chain, Vitronectin, and yon Willebrand Factor and Required for Binding to/33
PMID: 7525851
Gene: ITGA2B and/or ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: This article mentions a GT proband; however, no variants in ITGA2B and/or ITGB3 are mentioned therefore there is insufficient evidence
Thrombospondin-inducedAdhesionofHumanPlatelets
PMID: 2010551
Gene: ITGA2B and ITGB3
HGNC: 6138 and 6156
NoEvidence: This article does not mention Glanzmann thrombasthenia patients/probands with variants in ITGA2B and/or ITGB3; therefore, there is no evidence to report
A naturally occurring Tyr143HisαIIb mutation abolishes αIIbβ3 function for soluble ligands but retains its ability for mediating cell adhesion and clot retraction: comparison with other mutations causing ligand-binding defects
PMID: 12506038
Gene: ITGA2B
HGNC: 6138
A β3 Asp217→Val substitution in a patient with variant Glanzmann Thrombasthenia severely affects integrin αIIBβ3 functions
PMID: 18832906
Gene: ITGB3
HGNC: 6156
Identification of a nonsense mutation at amino acid 5 84-Arginine of platelet glycoprotein IIb in patients with type I Glanzmann thrombasthenia
PMID: 8485050
Gene: ITGA2B
HGNC: 6138
Study of the Relationship between HPA-1 and HPA-5 Gene Polymorphisms and Refractory to Platelet Therapy and Recombinant Factor VII in Glanzmann Thrombasthenia Patients in Southeast of Iran
PMID: 29951177
Gene: ITGA2B and ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: Article mentions Glanzmann thrombasthenia probands; however, no variants associated with patients therefore insufficient evidence
Glanzmann thrombasthenia and Bernard–Souliersyndrome in south Iran
PMID: 16178914
Gene: ITGA2B and/or ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: This article mentions various probands with GT; however, there are no mentioned variants in ITGA2B and/or ITGB3, therefore, we have insufficient evidence
Open aortic valve replacement in a patient with Glanzmann’sthrombasthenia: a multidisciplinary strategy to minimizeperioperative bleeding
PMID: 23710629
Genes: ITGA2B and/or ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: Mention of proband with Glanzmann thrombasthenia however no variants in the proband are mentioned for ITGA2B and ITGB3
Cytoskeletal perturbation leads to plateletdysfunction and thrombocytopenia in variantforms of Glanzmann thrombasthenia
PMID: 26452979
Gene: ITGB3
HGNC: 6156
InsufficientEvidence: This article mentions variants in ITGB3; however, there is no specific GT proband/patient information; therefore, there is insufficient evidence
An αIIb mutation in patients with Glanzmann thrombasthenia located in the N‐terminus of blade 1 of the β‐propeller (Asn2Asp) disrupts a calcium binding site in blade 6
PMID: 21029361
Gene: ITGA2B
HGNC: 6138
Note: Although article mention 4 probands being studied, the caption under Fig 1 with the pedigree states, "Shown are three of the four homozygous patients (lanes 2, 4 and 6), heterozygotes" therefore the 4th proband is not mentioned
Glanzmann’s Thrombasthenia: Identification of 19 New Mutations in 30 Patients
PMID: 12083483
Gene: ITGA2B and ITGB3
HGNC: 6138 and 6156
Created page notes for proband information because the table will not let me highlight the proband info
Identificationofafunctionallyimportantsequenceinthecytoplasmictailofintegrinf33byusingcell-permeablepeptideanalogs
PMID: 8876221
Gene: ITGB3
HGNC: 6156
InsufficientEvidence: This article mentions variants in ITGB3; however, there are no Glanzmann thrombasthenia patients mentioned harboring these variants; therefore, there is insufficient evidence
Labeling of the Internal Pool of GP IIb-IIIa in Platelets by c7E3 Fab Fragments (abciximab): Flow and Endocytic Mechanisms Contribute to the Transport
PMID: 10029591
Gene: ITGA2B and/or ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: This article mentions a case report of a GT patient in another article; however, this article does not specifically mention any GT case reports
PreviouslyPublished: PMID: 2180491 and PMID:
Glanzmann Thrombasthenia Associated with a 21–Amino Acid Deletion (Leu817-Gln837) in Glycoprotein IIb due to Abnormal Splicing in Exon 25
PMID: 15293575
Gene: ITGA2B
HGNC: 6138
Inherited mutations within the calcium-binding sites of the integrin orIIb subunit (platelet glycoprotein IIb) Effects of the amino acid side chain and the amino acid position on cation binding
PMID: 8925838
Gene: ITGA2B
HGNC: 6138
Integrin-Dependent Phosphorylation and Activation of the Protein Tyrosine Kinase pp125 FAr in Platelets
PMID: 1385445
Gene: ITGA2B and ITGB3
HGNC: 6138 and 6156
NoEvidence: This article does not mention Glanzmann thrombasthenia patients with variants in ITGA2B and/or ITGB3; therefore, there is no evidence to report
Human endoglin as a potential new partner involved in platelet–endothelium interactions
PMID: 29080903
Gene: ITGA2B and ITGB3
HGNC: 6138 and 6156
NoEvidence: No mention of patients with Glanzmann thrombasthenia or variants in probands. This article is about endoglin, an adhesion molecule involved in the interaction between endothelial cells and platelets through intigren recognition
αIIbβ3 variants defined by next-generation sequencing: Predicting variants likely to cause Glanzmann thrombasthenia
PMID: 25827233
Gene: ITGA2B and ITGB3
HGNC: 6138 and 6156, respectively
InsufficientEvidence: This article analyzed missense variants in the integrin αIIbβ3 receptor subunit genes ITGA2B and ITGB3 identified by WES comprising around 32,000 alleles from 16,108 individuals. There is no specific tie between variants and probands; therefore, there is insufficient evidence
Proteolysis of Platelet Cortactin by Calpain*
PMID: 9235918
Gene: ITGA2B and/or ITGB3
HGNC: 6138 and 6156, respectively
NoEvdidence: This article does not mention Glanzmann thrombasthenia patients/probands with variants in ITGA2B and/or ITGB3; therefore, there is no evidence to report
Diagnosis of Disorders of Platelet Function by Flow Cytometry
PMID: 12840847
Gene: ITGA2B and/or ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: This article mentions two probands with GT; however, no variants in ITGA2B and/or ITGB3 were mentioned
Glanzmann Thrombasthenia: State of the Art and Future Directions
PMID: 23929305
Gene: ITGA2B and ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: This article is a review on GT; there are several previously published probands; however, there are no new case reports in this article.
A genetic analysis of integrin function: Glanzmannthrombastheniain vitro
PMID: 9050889
Gene: ITGA2B and ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: This article mentions ITGA2B/ITGB3 variants and has experimental evidence; however, no GT cases reports are mentioned here
Note: Previously published articles are mentioned here, they have been tagged
Successful unrelated donor cord blood transplantation for Glanzmann’s thrombasthenia Carrie L. Kitko Department of Pediatrics and Internal Medicine, Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, MISearch for more papers by this author John E. Levine Department of Pediatrics and Internal Medicine, Blood and Marrow Transplant Program, University of Michigan, Ann Arbor, MISearch for more papers by this author Dana C. Matthews Department of Pediatrics, University of Washington, Seattle, WASearch for more papers by this author Paul A. Carpenter Department of Pediatrics, University of Washington, Seattle, WA Fred Hutchinson Cancer Research Center, Seattle, WA, USASearch for more papers by this author
PMID: 19849809
Gene: ITGA2B and/or ITGB3
HGNC: 6138 and 6156
InsufficientEvidence: This article mentions patients with GT however no variants in ITGA2B and/or ITGB3 are mentioned here
Homozygous Point Mutations in Platelet Glycoprotein ITGA2B Gene as Cause of Glanzmann Thrombasthenia in 2 Families
PMID: 22513797
Gene: ITGA2B
HGNC: 6138
GDAP2 mutations implicate susceptibility to cellular stress in a new form of cerebellar ataxia
PMID: 30084953
Gene: GDAP2
HGNCID: HGNC:18010
H Syndrome: A Case Report and Review of Literature
PMID: 29527032
GeneName: SLC29A3
HGNC: HGNC:23096
Disease: H syndrome
MonDO ID: MONDO:0011273
Inheritance: AR
no genetic testing performed
H syndrome: The first 79 patients
PMID: 24172204
GeneName: SLC29A3
HGNC: HGNC:23096
Disease: H syndrome
MonDO ID: MONDO:0011273
Inheritance: AR
great review of cases to curate
B17 – B27
Case#: B17 - B27
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C Chr = 31, FVIII:AG = 90, 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.1636C>T
LegacyVariant:
ClinVar: No
CAID: CA255112
gnomAD:
Haemophilia A mutations in patients with non-severe phenotype associated with a discrepancy between one-stage and chromogenic factor VIII activity assays
PMID: 24452774
Gene: F8
HGNCID: 3546
A9 – A11
Case#: A9-A11
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 13, FVIII:AG = 28, 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.1648C>T
LegacyVariant:
ClinVar: No
CAID: CA255113
gnomAD:
B74
Case#: B74
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C Chr = 19, FVIII:AG = 17, 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.5325G>C, NM_000132.4:c.5325G>T
LegacyVariant:
ClinVar: No
CAID: CA255160, CA414910668
gnomAD:
A12
Case#: A12
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 28, FVIII:AG = 54, assay discrepancy present (OSA>CSA)
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: Coding region and intron/exon bound-aries of the F8 gene were amplified from all patient samples and directly sequenced using primers
Gene: F8
Variant: NM_000132.4:c.2045T>C
LegacyVariant:
ClinVar: No
CAID: CA414909247
gnomAD:
A16
Case#: A16
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 7, FVIII:AG = 23, assay discrepancy present (OSA>CSA)
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: Coding region and intron/exon bound-aries of the F8 gene were amplified from all patient samples and directly sequenced using primers
Gene: F8
Variant: NM_000132.4:c.5879G>A
LegacyVariant:
ClinVar: No
CAID: CA255019
gnomAD:
S27
Case#: S27, 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.3637delA
LegacyVariant:
ClinVar: No
CAID: CA255146
gnomAD:
S8
Case#: S8, Iranian
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Family history of HA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125, HP:0005261
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The F8 gene was directly sequenced for all 26 exons using the Sanger sequencing method. PCR was performed and subsequently analyzed
Gene: F8
Variant: NA
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
S16
Case#: S16, Iranian
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125, HP:0005261
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The F8 gene was directly sequenced for all 26 exons using the Sanger sequencing method. PCR was performed and subsequently analyzed
Gene: F8
Variant: NA
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
97
Case#: 97, male, 66 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.6517A>G
LegacyVariant:
ClinVar: No
CAID: CA414907348
gnomAD:
108
Case#: 108, male, 36 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
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.6870G>T
LegacyVariant:
ClinVar: No
CAID: CA414903147
gnomAD:
40
Case#: 40, male, 32 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 24.5%
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.871G>A
LegacyVariant:
ClinVar: No
CAID: CA414918134
gnomAD:
117
Case#: 117, male, 8 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.5219+1G>A
LegacyVariant:
ClinVar: 993734
CAID: CA414913420
gnomAD:
152
Case#: 152, male, 27 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 3.6%
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.2777delC
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
123
Case#: 123, male, 7 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6273+1G>T
LegacyVariant:
ClinVar: No
CAID: CA414902680
gnomAD:
175
Case#: 175, male, 32 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.del exons5_6
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
183
Case#: 183, male, 38 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.del exons15_26
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
101
Case#: 101, male, 7 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 3%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6611T>C
LegacyVariant:
ClinVar: No
CAID: CA414906072
gnomAD:
73
Case#: 73, male, 67 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 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.5422C>T
LegacyVariant:
ClinVar: 10278
CAID: CA255166
gnomAD:
164
Case#: 164, male, 43 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.4339delG
LegacyVariant:
ClinVar: No
CAID: CA873341376
gnomAD:
24
Case#: 24, male, 8 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
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.6666G>A
LegacyVariant:
ClinVar: No
CAID: CA414905572
gnomAD:
142
Case#: 142, male, 22 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
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.599_601delAAG
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
10
Case#: 10, male, 9 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
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.1596G>A
LegacyVariant:
ClinVar: No
CAID: CA414912044
gnomAD:
42
Case#: 42, male, 24 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 1.2%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.901C>T
LegacyVariant:
ClinVar: No
CAID: CA414917990
gnomAD:
166
Case#: 166, male, 12 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.4379delA
LegacyVariant:
ClinVar: No
CAID: CA255151
gnomAD:
26
Case#: 26, male, 13 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6976C>T
LegacyVariant:
ClinVar: 10085
CAID: CA255007
gnomAD:
36
Case#: 36, male, 10 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.387G>C
LegacyVariant:
ClinVar: No
CAID: CA414919866
gnomAD:
139
Case#: 139, male, 17 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.dup exons7_22
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
115
Case#: 115, male, 37 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.1271+1G>A
LegacyVariant:
ClinVar: 811704
CAID: CA414915622
gnomAD:
13
Case#: 13, male, 24 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.1861C>T
LegacyVariant:
ClinVar: No
CAID: CA414910596
gnomAD:
16
Case#: 16, male, 22 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.2404C>T
LegacyVariant:
ClinVar: No
CAID: CA414901774
gnomAD:
161
Case#: 161, male, 8 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 1.5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.3637delA
LegacyVariant:
ClinVar: No
CAID: CA255146
gnomAD:
88
Case#: 88, male, 29 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 2%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.6406G>A
LegacyVariant:
ClinVar: No
CAID: CA414899430
gnomAD:
80
Case#: 80, male, 52 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 10.9%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.5707G>A
LegacyVariant:
ClinVar: No
CAID: CA414907751
gnomAD:
56
Case#: 56, male, 12 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 29%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.1834C>T
LegacyVariant:
ClinVar: 10236
CAID: CA255129
gnomAD:
69
Case#: 69, male, 11 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 1.1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.5321A>T
LegacyVariant:
ClinVar: No
CAID: CA414910719
gnomAD:
34
Case#: 34, male, 25 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.382T>C
LegacyVariant:
ClinVar: 811825
CAID: CA414919878
gnomAD:
75
Case#: 75, male, 14 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 16.5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.5545T>A
LegacyVariant:
ClinVar: No
CAID: CA414908552
gnomAD:
179
Case#: 179, male, 11 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.del exon14
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
146
Case#: 146, male, 13 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.209_212delTTGT
LegacyVariant:
ClinVar: No
CAID: CA255050
gnomAD:
61
Case#: 61, male, 7 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.2066T>C
LegacyVariant:
ClinVar: No
CAID: CA414909145
gnomAD:
132
Case#: 132, male, 28 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 2.7%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.4379dupA
LegacyVariant:
ClinVar: No
CAID: CA645292749
gnomAD:
7
Case#: 7, male, 8 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.1063C>T
LegacyVariant:
ClinVar: 10139
CAID: CA255031
gnomAD:
45
Case#: 45, male, 75 years old, Chinese
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 6.5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.1172G>A
LegacyVariant:
ClinVar: 10111
CAID: CA120918
gnomAD:
157
Case#: 157, male, 30 years old, Chinese
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C = 1.2%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.3637delA
LegacyVariant:
ClinVar: No
CAID: CA255146
gnomAD:
1
Case#: 1, male, 30 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.36C>A
LegacyVariant:
ClinVar: No
CAID: CA414920668
gnomAD:
84
Case#: 84, male, 48 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.5821A>C
LegacyVariant:
ClinVar: No
CAID: CA414906679
gnomAD:
20
Case#: 20, male, 36 years old, Chinese
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Noted Family History
ParentalTesting: Maternity confirmed
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: F8 gene variants were identified using next-generation sequencing (NGS), inverse shifting PCR and MLPA
Gene: F8
Variant: NM_000132.3:c.5953C>T
LegacyVariant:
ClinVar: 10300
CAID: CA255191
gnomAD:
c.1538G>T
Case#: 21
DiseaseAssertion: Hemophilia A
FamilyInfo: Positive
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Moderate
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.1538G>T (p.Gly494Val)
ClinVar: NA
CAID: CA414912397
gnomAD: Not reported
IVS15 g-1c
Case#: 11
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.5374-1G>C
ClinVar: NA
CAID: CA414909191
gnomAD: NA
C.6515C>T
Case#: 29
DiseaseAssertion: Hemophilia A
FamilyInfo: Positive
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.6515C>T (p.Pro2153Leu)
ClinVar: NA
CAID: CA414907354
gnomAD: Not reported
c.556G>A
Case#: 13
DiseaseAssertion: Hemophilia A
FamilyInfo: Positive
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.556G>A
ClinVar: NA
CAID: CA414919461
gnomAD: Not reported
Identification of 31 novel mutations in the F8 gene in Spanish hemophilia A patients: structural analysis of 20 missense mutations suggests new intermolecular binding sites
PMID: 18184865
Gene: F8
HGNCID: 3546
C.7006A>T
Case#: 31
DiseaseAssertion: Hemophilia A
FamilyInfo: Positive
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Moderate
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.7006A>T (p.Ile2317Phe)
ClinVar: NA
CAID: CA414896884
gnomAD: Not reported
c.1682delA
Case#: 2
DiseaseAssertion: Hemophilia A
FamilyInfo: Sporadic
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.1682del (p.Asp561ValfsTer2)
ClinVar: NA
CAID: CA1139532041
gnomAD: Not reported
c.5159C>T
Case#: 24
DiseaseAssertion: Hemophilia A
FamilyInfo: Positive
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Mild
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.5159C>T (p.Ala1701Val)
ClinVar: NA
CAID: CA414913679
gnomAD: Not reported
c.248C>G
Case#: 12
DiseaseAssertion: Hemophilia A
FamilyInfo: Positive
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Mild
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.248C>G (p.Pro83Arg)
ClinVar: NA
CAID: CA10568618
gnomAD: MAF for Pro83Arg in the Ashkenazi Jewish population 0.0001335<br>https://gnomad.broadinstitute.org/variant/X-154227771-G-C?dataset=gnomad_r2_1
c.1487C>G
Case#: 20
DiseaseAssertion: Hemophilia A
FamilyInfo: Sporadic
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe
CasePreviousTesting: All 26 exons and exon-intron boundaries of the F8 gene were amplified using primers and PCR, analyzed by direct forward and reverse sequencing using a DNA sequencing kit
Gene: F8
Variant: NM_000132.3:c.1487C>G (p.Pro477Arg)
ClinVar: NA
CAID: CA414912766
gnomAD: Not reported
004–2009
Case#: 004-2009
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.1899G>T
LegacyVariant:
ClinVar: No
CAID: CA414910251
gnomAD:
003–2003
Case#: 003-2003
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.5275G>A
LegacyVariant:
ClinVar: No
CAID: CA414911087
gnomAD:
009–1006
Case#: 009-1006
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.822G>A
LegacyVariant:
ClinVar: No
CAID: CA255072
gnomAD:
071–2015
Case#: 071-2015
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.2710dupC
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
071–1037
Case#: 071-1037
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 1% < FVIII:C < 5%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.3169G>A
LegacyVariant:
ClinVar: No
CAID: CA255144
gnomAD:
020–2023
Case#: 020-2023
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.5312T>C
LegacyVariant:
ClinVar: No
CAID: CA414910786
gnomAD:
002–2005
Case#: 002-2005
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.217T>C
LegacyVariant:
ClinVar: No
CAID: CA414920251
gnomAD:
060–2007
Case#: 060-2007
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.5399G>A
LegacyVariant:
ClinVar: No
CAID: CA255162
gnomAD:
044–2001
Case#: 044-2001
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.6344delT
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
001–1038
Case#: 001-1038
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.6065G>A
LegacyVariant:
ClinVar: No
CAID: CA414904814
gnomAD:
038–1013
Case#: 038-1013
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:
022–2004
Case#: 022-2004
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1492G>A
LegacyVariant:
ClinVar: No
CAID: CA255109
gnomAD:
001–2039
Case#: 001-2039
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.5156T>C
LegacyVariant:
ClinVar: No
CAID: CA414913690
gnomAD:
015–2005
Case#: 015-2005
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.3637delA
LegacyVariant:
ClinVar: No
CAID: CA255146
gnomAD:
071–1015
Case#: 071-1015
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:
035–2003
Case#: 035-2003
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.4825dupA
LegacyVariant:
ClinVar: No
CAID: CA255152
gnomAD:
028–1002
Case#: 028-1002
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant:
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
071–2029
Case#: 071-2029
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1697T>A
LegacyVariant:
ClinVar: No
CAID: CA414911721
gnomAD:
035–2007
Case#: 035-2007
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1963_1964insT
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
002–2017
Case#: 002-2017
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.941C>T
LegacyVariant:
ClinVar: No
CAID: CA414917829
gnomAD:
071–2010
Case#: 071-2010
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1208A>C
LegacyVariant:
ClinVar: No
CAID: CA414916134
gnomAD:
001–1060
Case#: 001-1060
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.686C>G
LegacyVariant:
ClinVar: No
CAID: CA414919141
gnomAD:
047–1020
Case#: 047-1020
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 1% < FVIII:C < 5%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.3169G>A
LegacyVariant:
ClinVar: No
CAID: CA255144
gnomAD:
091–2009
Case#: 091-2009
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.2681delG
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
003–2024
Case#: 003-2024
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.5399G>A
LegacyVariant:
ClinVar: No
CAID: CA255162
gnomAD:
071–1036
Case#: 071-1036
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 1% < FVIII:C < 5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant:
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
060–2010
Case#: 060-2010
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1834C>T
LegacyVariant:
ClinVar: No
CAID: CA255129
gnomAD:
020–2024
Case#: 020-2024
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.437A>C
LegacyVariant:
ClinVar: No
CAID: CA414919724
gnomAD:
001–2027
Case#: 001-2027
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%, Inhibitor present
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1869_1870delG
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
015–2003
Case#: 015-2003
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.3637delA
LegacyVariant:
ClinVar: No
CAID: CA255146
gnomAD:
020–2006
Case#: 020-2006
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.1492G>A
LegacyVariant:
ClinVar: No
CAID: CA255109
gnomAD:
035–2022
Case#: 035-2022
DiseaseAssertion: Hemophilia A, mild
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 5% < FVIII:C < 40%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.5954G>A
LegacyVariant:
ClinVar: No
CAID: CA414905715
gnomAD:
020–2027
Case#: 020-2027
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.5253A>C
LegacyVariant:
ClinVar: No
CAID: CA414911240
gnomAD:
091–2008
Case#: 091-2008
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 1% < FVIII:C < 5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.142A>G
LegacyVariant:
ClinVar: No
CAID: CA414920432
gnomAD:
001–2051
Case#: 001-2051
DiseaseAssertion: Hemophilia A, moderate
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: 1% < FVIII:C < 5%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.2134C>A
LegacyVariant:
ClinVar: No
CAID: CA414904092
gnomAD:
042–1001
Case#: 042-1001
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 1%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: The 26 exons and their flanking regions of F8 were amplified by PCR using specific primers with a simple modification
Gene: F8
Variant: NM_000132.3:c.2144+2A>G
LegacyVariant:
ClinVar: No
CAID: No
gnomAD:
c.1219T>C
Case#: 40
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C <1% (Severe Phenotype)
CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing
Gene: F9
Variant: NM_000133.3:c.1219T>C (p.Cys407Arg)
ClinVar: NA
CAID: CA414446562
gnomAD: Not reported
c1834C>T
Case#: 15
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 17/19/25% (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.1834C>T (p.Arg612Cys)
ClinVar: 10236 https://www.ncbi.nlm.nih.gov/clinvar/variation/10236/
CAID: CA255129
gnomAD: MAF for Arg612Cys in Latino population 0.0001458<br>https://gnomad.broadinstitute.org/variant/X-154182236-G-A?dataset=gnomad_r2_1
c.6533G>A
Case#: 32
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 28%, 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.6533G>A (p.Arg2178His)
ClinVar: 10319 https://www.ncbi.nlm.nih.gov/clinvar/variation/10319/
CAID: CA255212
gnomAD: MAF for Arg2178His in the African population 0.00007598<br>https://gnomad.broadinstitute.org/variant/X-154091399-C-T?dataset=gnomad_r2_1
c.518C>T
Case#: 43
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C <1% (Severe Phenotype)
CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing
Gene: F9
Variant: NM_000133.3:c.518C>T (p.Ala173Val)
ClinVar: NA
CAID: CA414439510
gnomAD: Not reported
c.6622C>G
Case#: 33
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 21/29/33/15/20/26%, Mild Phenotype, No inhibitors present
CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing
Gene: F8
Variant: NM_000132.3(F8):c.6622C>G (p.Gln2208Glu)
ClinVar: 811219 https://www.ncbi.nlm.nih.gov/clinvar/variation/811219/
CAID: CA414905992
gnomAD: MAF for Gln2208Glu in the Other population 0.0002208<br>https://gnomad.broadinstitute.org/variant/X-154090094-G-C?dataset=gnomad_r2_1
c.1649G>A
Case#: 14
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 27% (Mild Phenotype), No inhibitors present
CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing
Gene: F8
Variant: NM_000132.3(F8):c.1649G>A (p.Arg550His)
ClinVar: 10225 https://www.ncbi.nlm.nih.gov/clinvar/variation/10225/
CAID: CA255115
gnomAD: MAF for Arg550His in European (non-Finnish) population 0.00002442<br> https://gnomad.broadinstitute.org/variant/X-154185335-C-T?dataset=gnomad_r2_1
c.280A>G
Case#: 2
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 32% (Mild Phenotype), No inhibitors present
CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing
Gene: F8
Variant: NM_000132.3(F8):c.280A>G (p.Thr94Ala)
ClinVar: NA
CAID: CA10568603
gnomAD: MAF for Thr94Ala in the European (Non-Finnish) population 0.00001222<br> https://gnomad.broadinstitute.org/variant/X-154225356-T-C?dataset=gnomad_r2_1
c.7031G>C
Case#: 38
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 29%, Mild Phenotype, No inhibitors present
CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing
Gene: F8
Variant: NM_000132.3:c.7031G>C (p.Gly2344Ala)
ClinVar: NA
CAID: CA414896685
gnomAD: Not reported
c.6118T>G
Case#: 29
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVIII:C 10/8/14%, Mild Phenotype, No inhibitors present
CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing
Gene: F8
Variant: NM_000132.3:c.6118T>G (p.Cys2040Gly)
ClinVar: NA
CAID: CA414904332
gnomAD: Not reported
c.422G>A
Case#: 42
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FIX:C 4% (Moderate Phenotype)
CasePreviousTesting: Screened for IVS-22 and IVS-1, sample was blinded for NGS and the sequencing component was validated by comparing results with Sanger Sequencing
Gene: F9
Variant: NM_000133.4(F9):c.422G>A (p.Cys141Tyr)
ClinVar: 811510 https://www.ncbi.nlm.nih.gov/clinvar/variation/811510/
CAID: CA414438897
gnomAD: Not reported
UQU-HB1
Case#: UQU-HB1, Male, 2-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe, PTT 74.5
CasePreviousTesting: Screened for all factor IX exons by capillary sequencing
Gene: F9
Variant: NM_000133.3(F9):c.1136G>A (p.Arg379Gln)
ClinVar: 10613 https://www.ncbi.nlm.nih.gov/clinvar/variation/10613/
CAID: CA255394
gnomAD: Not reported
UQU-HB8
Case#: UQU-HB8, Male, 1-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe, Disabled both knees , PTT 105.1
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-HA35
Case#: UQU-HA35, Male, 2-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: PTT 118.8, Disabled both knees, Severe
CasePreviousTesting: Screened for inversion 22 by inverse PCR, screened for inversion 1 by multiplexed PCR, capillary sequencing (Sanger method) was performed for factor VIII all 26 exons
Gene: F8
Variant: NM_000132.3:c.1835G>C (p.Arg612Pro)
ClinVar: NA
CAID: CA414910775
gnomAD: Not reported
UQU-HB7
Case#: UQU-HB7, Male, 16-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: Severe, Disabled right knee and both ankles , PTT 53.2
CasePreviousTesting: Screened for all factor IX exons by capillary sequencing
Gene: F9
Variant: NM_000133.3(F9):c.880C>T (p.Arg294Ter)
ClinVar: 10587 https://www.ncbi.nlm.nih.gov/clinvar/variation/10587/
CAID: CA255344
gnomAD: Not reported
UQU-HA36
Case#: UQU-HA36, Male, 6-months-old, Saudi Arabia
DiseaseAssertion: Hemophilia A
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: PTT 125.4, Severe, Disabled right knees, left elbow, and ankle
CasePreviousTesting: Screened for inversion 22 by inverse PCR, screened for inversion 1 by multiplexed PCR, capillary sequencing (Sanger method) was performed for factor VIII all 26 exons
Gene: F8
Variant: NM_000132.3:c.409A>C (p.Thr137Pro)
ClinVar: NA
CAID: CA414919795
gnomAD: Not reported
Genetic determinants of VWF clearance and FVIII binding modify FVIII pharmacokinetics in pediatric hemophilia A patients
PMID: 31350267
Gene: F8
HGNC: 3546
InsufficientEvidence: This article groups together all 43 patients so there are no individual case reports that are mentioned
Assay discrepancy in mild haemophilia A due to a factor VIII missense mutation (Asn694Ile) in a large Danish family R. Schwaab, Institute for Experimental Haematology and Transfusion Medicine, Sigmund-Freud-Str. 25, 53105 Bonn, Germany,Search for more papers by this authorJ. Oldenburg, Institute for Experimental Haematology and Transfusion Medicine, Sigmund-Freud-Str. 25, 53105 Bonn, Germany, Department of Human Genetics, Biozentrum, Am Hubland, 97074 Würzburg, Germany,Search for more papers by this authorG. Kemball-Cook, Haemostasis Research Group, MRC Clinical Sciences Centre, Imperial College Medical School, Hammersmith Hospital, Du Cane Road, London W12 0NN, UK, andSearch for more papers by this authorT. Albert, Institute for Experimental Haematology and Transfusion Medicine, Sigmund-Freud-Str. 25, 53105 Bonn, Germany,Search for more papers by this authorC. Juhler, University Hospital Skejby, Department of Clinical Immunology, Centre for Haemophilia and Thrombosis, DK-8200 Aarhus N, Denmark Search for more papers by this authorP. Hanfland, Institute for Experimental Haematology and Transfusion Medicine, Sigmund-Freud-Str. 25, 53105 Bonn, Germany,Search for more papers by this authorJ. Ingerslev, University Hospital Skejby, Department of Clinical Immunology, Centre for Haemophilia and Thrombosis, DK-8200 Aarhus N, Denmark Search for more papers by this author
PMID: 10886198
Gene: F8
HGNCID: 3546
A 68-year-old male was diagnosed with severe HEMA in early childhood
Case#: 68 year old male
DiseaseAssertion: Hemophilia A, severe
FamilyInfo: Mother was a carrier and brother also suffered from severe Hemophilia A
ParentalTesting: No
CasePresentingHPOs: HP:0003125
CaseHPOFreeText: FVIII:C < 0.001%
CaseNotHPOs: NA
CaseNotHPOFreeText: NA
CasePreviousTesting: Whole exome sequencing was performed and subsequently analyzed
Gene: F8
Variant: NM_000132.3:c.5411_5413del
LegacyVariant:
ClinVar: No
CAID: NA
gnomAD:
Preconception Carrier Screening by Genome Sequencing: Results from the Clinical Laboratory
PMID: 29754767
Gene: F8
HGNC: 3546
InsufficientEvidence: This article mentions a F8 variant however does not have a detailed case report for a proband
Table 1
Case#: Cz6, Italy (Calabria)
DiseaseAssertion: Hemophilia A
FamilyInfo: Sporadic
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVII:C <1%
CasePreviousTesting: Polymerase chain reaction (PCR) analysis, Long PCR for detecting the intron 22 inversion was performed, Direct cycle sequence analysis using the Taq dye-deoxy terminator method
Gene: F8
Variant: NM_000132.3(F8):c.4156C>T (p.Gln1386Ter)
ClinVar: NA
CAID: CA414891965
gnomAD: Not reported
Table 2
Case#: Cz40, Italy (Calabria)
DiseaseAssertion: Hemophilia A
FamilyInfo: Inherited
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVII:C 2.5%
CasePreviousTesting: Polymerase chain reaction (PCR) analysis, Long PCR for detecting the intron 22 inversion was performed, Direct cycle sequence analysis using the Taq dye-deoxy terminator method
Gene: F8
Variant: NM_000132.3:c.1538-18G>A
ClinVar: 811357 https://www.ncbi.nlm.nih.gov/clinvar/variation/811357/
CAID: CA873354114
gnomAD: Not reported
Table 2
Case#: Cz5, Italy (Calabria)
DiseaseAssertion: Hemophilia A
FamilyInfo: Inherited
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVII:C 4%
CasePreviousTesting: Polymerase chain reaction (PCR) analysis, Long PCR for detecting the intron 22 inversion was performed, Direct cycle sequence analysis using the Taq dye-deoxy terminator method
Gene: F8
Variant: NM_000132.3:c.1538-18G>A
ClinVar: 811357 https://www.ncbi.nlm.nih.gov/clinvar/variation/811357/
CAID: CA873354114
gnomAD: Not reported
Table 2
Case#: Cz13, Italy (Calabria)
DiseaseAssertion: Hemophilia A
FamilyInfo: Inherited
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVII:C 4%
CasePreviousTesting: Polymerase chain reaction (PCR) analysis, Long PCR for detecting the intron 22 inversion was performed, Direct cycle sequence analysis using the Taq dye-deoxy terminator method
Gene: F8
Variant: NM_000132.3:c.1538-18G>A
ClinVar: 811357 https://www.ncbi.nlm.nih.gov/clinvar/variation/811357/
CAID: CA873354114
gnomAD: Not reported
Table 1
Case#: Cz7, Italy (Calabria)
DiseaseAssertion: Hemophilia A
FamilyInfo: Sporadic
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVII:C <1%
CasePreviousTesting: Polymerase chain reaction (PCR) analysis, Long PCR for detecting the intron 22 inversion was performed, Direct cycle sequence analysis using the Taq dye-deoxy terminator method
Gene: F8
Variant: NM_000132.3(F8):c.5143C>T (p.Arg1715Ter)
ClinVar: 10267 https://www.ncbi.nlm.nih.gov/clinvar/variation/10267/
CAID: CA255155
gnomAD: Not reported
Table 2
Case#: Cz16, Italy (Calabria)
DiseaseAssertion: Hemophilia A
FamilyInfo: Sporadic
ParentalTesting: NA
CasePresentingHPOs: NA
CaseHPOFreeText: FVII:C 4%
CasePreviousTesting: Polymerase chain reaction (PCR) analysis, Long PCR for detecting the intron 22 inversion was performed, Direct cycle sequence analysis using the Taq dye-deoxy terminator method
Gene: F8
Variant: NM_000132.3:c.1538-18G>A
ClinVar: 811357 https://www.ncbi.nlm.nih.gov/clinvar/variation/811357/
CAID: CA873354114
gnomAD: Not reported
9-month old boy was diagnosed with severe haemophilia B
Case1: Male, 9-months at time of diagnosis
DiseaseAssertion: Severe Hemophilia B
FamilyInfo: NA
ParentalTesting: NA
CasePresentingHPOs: HP:0001933 (Subcutaneous hemorrhage), HP:0007420 (Spontaneous hematomas), HP:0012233 (Intramuscular hematoma), HP:0005261 (Joint hemorrhage)
CaseHPOFreeText: FIX: C <1%, recurrent anaphylactic reactions to FIX (abdominal pain, respiratory arrest, and severe hypotension)
CasePreviousTesting: F9 analysis (revealed a point mutation at exon H)
Gene: F9
Variant: NM_000133.3(F9):c.880C>T (p.Arg294Ter)
LegacyVariant: g 30863 C>T; Arg 248 stop
ClinVar: 10587 https://www.ncbi.nlm.nih.gov/clinvar/variation/10587/
gnomAD: Not reported
Factor VIII: Long-established role in haemophilia A and emerging evidence beyond haemostasis
PMID: 30922616
Gene: F8
HGNC: 3546
InsufficientEvidence: This article is a review, it does not mention any new case reports
PreviouslyPublished
Genetic testing in the probands from two independent Slovenian families identified a novel variant c.3457T>A (Ter1153Lysext*38) in the RPGRORF15. The variant is predicted to disrupt the terminal codon of the RPGRORF15, resulting in a C-terminal extension of the protein by 38 aminoacids ending with a new stop codon. The variant has not been reported in the biomedical literature and is not present in the GnomAD population database (gnomad.broadinstitute.org, accessed on 06.01.2021). Single-nucleotide polymorphism analysis comparing X-chromosomes of the probands is shown in Figure 2C. On the X-chromosome we identified a large block of hemizygous SNPs shared by both probands with an estimated size of 29 megabases, which suggests that observation of an identical variant in two independent families may be due to a founder effect.
Case#: Hadalin_2021_Family_1_Patient_III-1, male, 31 years old at first examination, family origin in Slovenia
CasePresentingHPOs: HP:0011463 (Childhood onset), HP:0000545 (Myopia), HP:0008020 (Cone dystrophy), HP:0007663 (Reduced visual acuity), HP:0012230 (Rhegmatogenous retinal detachment), HP:0000603 (Central scotoma), HP:0007814 (Retinal pigment epithelial mottling), HP:0008043 (Retinal arteriolar constriction), HP:0000543 (Optic disc pallor), HP:0030602 (Abnormal fundus autofluorescence imaging), HP:0200070 (Peripheral retinal atrophy), HP:0030465 (Undetectable light-adapted electroretinogram), HP:0000613 (Photophobia), HP:0011504 (Bull's eye maculopathy), HP:0007737 (Bone spicule pigmentation of the retina),
CaseHPOFreeText: The patient received a diagnosis of cone dystrophy. Myopia was present from childhood, while visual loss occurred in the early 30's.
CaseNotHPOs: N/A
CaseNotHPOFreeText: Dark-adapted ERG was normal at the time of the study.
CasePreviousTesting: The patient and an apparently unrelated proband from another family were subjected to whole-exome sequencing.
CaseMethod1: Whole-exome sequencing
CaseMethod2: Haplotype analysis using SNPs on the X chromosome
CaseGenotypingMethod: The patient and a proband from another family not known to be related were subjected to whole-exome sequencing, followed by haplotype analysis using SNPs on the X chromosome.
Variant: The patient harbors the NM_001034853.2(RPGR):c.3457T>A (p.Ter1153Lys) variant in the hemizygous state.
ClinVar: 931960
gnomAD: This variant was not found in gnomAD v.2.1.1.
VariantEvidence: NM_001034853.2(RPGR):c.3457T>A (p.Ter1153Lys) is a stop-loss variant that triggers an extension of the C-terminus of RPGR by 38 amino acids. It is not predicted to undergo nonsense-mediated decay, and its inheritance pattern with largely unaffected female carriers is consistent with loss-of-function.
CaseAddInfo: The proband is a member of Family 1, with the mother being a female carrier with mild myopia, and an apparently affected maternal grandfather. Two other patients not known to be close relatives but harboring the same founder variant within a 29-megabase shared region received the same diagnosis of cone dystrophy.
CasePMIDs: N/A
IRD can be inherited as autosomal recessive (AR)
Case#: Jespersgaard_2019_Patient_165, gender and age not specified, origin likely to be Danish based on cohort
CasePresentingHPOs: N/A
CaseHPOFreeText: The proband has been diagnosed with retinitis pigmentosa, as part of a larger group of generalized non-syndromic retinal dystrophies. Detailed phenotypes are not described.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: Next-generation sequencing was performed focusing on a targeted panel of 125 genes known to be linked to inherited retinal disease.
CaseMethod1: NGS panel
CaseMethod2: N/A
CaseGenotypingMethod: Next-generation sequencing was performed focusing on a targeted panel of 125 genes known to be linked to inherited retinal disease. It is not clear whether Sanger sequencing was used to validate the genotyping of this particular case.
Variant: The proband harbors the NM_000440.3(PDE6A):c.1620+1G>A variant in the homozygous state.
ClinVar: 636054
gnomAD: The NM_000440.3(PDE6A):c.1620+1G>A variant is found in gnomAD v2.1.1 at a frequency of 0.00003267 (1/30608) in the South Asian population https://gnomad.broadinstitute.org/variant/5-149275918-C-T
VariantEvidence: The NM_000440.3(PDE6A):c.1620+1G>A variant disrupts a canonical splice site in intron 12, but does not have experimental confirmation of exon skipping or frameshift.
CaseAddInfo: N/A
CasePMIDs: N/A
Herein, we report the identification of a novel nonsense mutation in the second exon of the KCNJ13 gene that leads to a premature stop codon in association with LCA16. We have determined that the mutation results in a severe truncation of the Kir7.1 C-terminus, alters protein localization, and disrupts potassium currents. Coexpression of the mutant and wild-type channel has no negative influence on the wild-type channel function, consistent with the normal clinical phenotype of carrier individuals.
Case#: Pattnaik_2015_Proband, male, age 10 years, family national origin described as Jordanian
CasePresentingHPOs: Nyctalopia HP:0000662, Childhood onset HP:0011463, Severely reduced visual acuity HP:0001141, Granular macular appearance HP:0007793, Retinal arteriolar constriction HP:0008043, Retinal degeneration HP:0000546, Abnormal choroid morphology (hypertrophy) HP:0000610
CaseHPOFreeText: The proband has been diagnosed at different times with Stargardt disease, retinitis pigmentosa, cone-rod dystrophy, and Leber congenital amaurosis, first presenting with night vision difficulties at age 2 years. Small focal sub-RPE deposits were observed.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: The proband was initially genotyped by PCR-based screening for known LCA-associated variants and next-generation sequencing focused on a 19-gene LCA panel.
CaseMethod1: PCR-based screening for known LCA-associated variants as well as next-generation sequencing of a 19-gene LCA panel
CaseMethod2: Sanger sequencing of gaps and low-coverage regions as well as for confirmation of the variants detected by other methods.
CaseGenotypingMethod: The proband was initially genotyped by PCR-based screening for known LCA-associated variants and next-generation sequencing focused on a 19-gene LCA panel. Sanger sequencing of gaps and low-coverage regions as well as for confirmation of the variants detected by other methods.
Variant: The individual is homozygous for the NM_002242.4(KCNJ13):c.158G>A (p.Trp53Ter) variant.
ClinVar: 224857
gnomAD: The variant is not found in gnomAD version 4.1.0.
VariantEvidence: Heterologous expression of the NM_002242.4(KCNJ13):c.158G>A (p.Trp53Ter) variant in CHO-K1 cells revealed that the variant channel retained very little ability to enable the flow of current, with the measurement of -68.8pA more comparable to the negative control (-42.4pA) than to the wild-type control (-588.7pA).
CaseAddInfo: The family history does not reportedly indicate consanguinity.
CasePMIDs: N/A
We have identified two Asian families with two novel homozygous mutations in the CLN5 gene.
GroupName: Lebrun_2009_Group_1
GroupPresentingHPOs: HP:0001251 (Ataxia), HP:0001250 (Seizure), HP:0002463 (Language impairment), HP:0011463 (Childhood onset)
GroupNotHPOs: N/A
NumberMales: 3
NumberFemales: 1
CountryOrigin: One family is from the United Kingdom, while the other family's country of origin is not mentioned
Ethnicity: One family is of Pakistani ethnic origin, while the second family is of Afghan ethnic origin
Race: Not clearly described, but both families have origins within a similar region of Asia.
AgeRange: Onset occurred between the ages of 2 and 5
TotalNumber: 4
FamilyInfo: 4
NoFamily: 0
VariantCount: 4
NonVariant: 0
OtherVariant: 0
GroupPreviousTesting: Genome-wide methods were not initially used, as clinical phenotypes were consistent with diagnosis of neuronal ceroid lipofuscinosis (NCL). Enzymatic tests ruled out defects in the CLN1, CLN2, and CLN10 loci, while CLN3, CLN6, and CLN8 defects were ruled out by Sanger sequencing of the coding regions. SNP array-based homozygosity mapping was performed, revealing 7 homozygous candidate regions in the affected members from the (consanguineous) family. These regions were analyzed for candidate NCL genes, finding CLN5 as the most likely locus to harbor the causative variant.
GroupMethod1: SNP array-based homozygosity mapping was performed, revealing 7 homozygous candidate regions in the affected members from the (consanguineous) family. These regions were analyzed for candidate NCL genes, finding CLN5 as the most likely candidate for further genotyping.
GroupMethod2: N/A
GroupGenotypingMethod: CLN5 mRNA was reverse transcribed, PCR-amplified, and subjected to Sanger sequencing.
GroupAddInfo: N/A
No evidence for a founder allele was found for the families carrying the stop mutation C35X (Fig. 2b).
Case#: Pusch_2000_Familly_9606_Proband, male, age and race not mentioned
CasePresentingHPOs: HP:0030640 (Complete congenital stationary night blindness), HP:0007663 (Reduced visual acuity), HP:0031624 (Moderate myopia), HP:0007984 (Electronegative electroretinogram)
CaseHPOFreeText: ERG with absent oscillatory-potential wavelets
CaseNotHPOs: HP:0001098 (Abnormal fundus morphology), HP:0030473 (Abnormal light-adapted flicker electroretinogram)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
CaseMethod1: Sanger sequencing of PCR amplified exons from NYX
CaseMethod2: N/A
CaseGenotypingMethod: The proband and family members were subjected to Sanger sequencing of NYX to identify the variant.
Variant: The proband harbors the NM_001378477.3(NYX):c.90C>A (p.Cys30Ter) variant on the X chromosome.
ClinVar: 11422
gnomAD: NM_001378477.3(NYX):c.90C>A (p.Cys30Ter) was not found in gnomAD.
VariantEvidence: This nonsense variant is located in exon 2/3 and is predicted to trigger NMD. It introduces a premature stop codon that would truncate 93% of the protein product.
CaseAddInfo: This variant appears not only in Family 9606, but also in Family 2438T, yet is not suspected to be a founder alelle.
CasePMIDs: N/A
PDE6C hydrolyzed cGMP with a Km of 65 ± 6 μm and kcat of 4400 ± 300 s−1 (Fig. 7A).
Selection B- Gene function is consistent with phenotype.
GOterm: GO:0047555 (3',5'-cyclic-GMP phosphodiesterase activity)
FunctionalEvidence: Purified PDE6C hydrolyzed cGMP with a Km and kcat slightly lower than trypsin-activated bovine rod PDE6 (Figure 7A).
FunctionalHPO: HP:0000551 (Color vision defect), HP:0030465 (Undetectable light-adapted electroretinogram)
An 18-year old highly myopic woman presented with bilateral retinoschisis associated with a unilateral macular hole in the right eye and vitreomacular traction in the left eye. Methods: Genetic studies disclosed a heterozygous pathogenic variant in the KCNJ13 gene was identified (c.484C>T (p.Arg162Trp)), consistent with a diagnosis of snowflake vitreoretinal degeneration (SVD). Results: While there were no corneal guttata, juvenile cataracts, or perivascular sheathing in this case, salient features of SVD included a fibrillar vitreous structure, crystalline retinopathy, and flattened optic nerves. The patient developed a FTMH in the left eye at 17 months follow up, followed by a rhegmatogenous retinal detachment (RRD) requiring 2 surgical repairs.
Case#: Ashkenazy_2023_Proband, female, age 18 at time of report, family origin unknown due to adoption but reported in the United States
CasePresentingHPOs: Snowflake vitreoretinal degeneration HP:0011533, High myopia HP:0011003, Retinoschisis HP:0030502, Rhegmatogenous retinal detachment HP:0012230, Abnormal vitreous humor morphology HP:0004327, Full-thickness macular hole HP:0031152
CaseHPOFreeText: The patient exhibited fibrillar vitreous structure, crystalline retinopathy, and optic nerve flattening.
CaseNotHPOs: Corneal guttata HP:0012038, Presenile cataracts HP:0007819
CaseNotHPOFreeText: Perivascular sheathing was absent.
CasePreviousTesting: Genotyping of the proband was not described in detail, but reportedly did not include whole exome sequencing, due to the specificity of the phenotype. Genes implied to have been possibly examined were COL2A1, COL11A1, and CSPG2.
CaseMethod1: Sanger sequencing of KCNJ13
CaseMethod2: N/A
CaseGenotypingMethod: Genotyping of the proband was not described in detail, but reportedly did not include whole exome sequencing, due to the specificity of the phenotype. Genes implied to have been possibly examined were COL2A1, COL11A1, and CSPG2. Sanger sequencing of KCNJ13 was performed.
Variant: The individual harbors the NM_002242.4(KCNJ13):c.484C>T (p.Arg162Trp) variant in the heterozygous state.
ClinVar: 6585
gnomAD: The variant is found in gnomAD version 4.1.0 at a frequency of 0.0000008536 (1 / 1,171,470) in the European (non-Finnish) population https://gnomad.broadinstitute.org/variant/chr2-232768790-G-A?dataset=gnomad_r4
VariantEvidence:NM_002242.4(KCNJ13):c.484C>T (p.Arg162Trp) is a missense variant that has functional evidence of electrophysiological abnormalities and loss of sensitivity to different K+ concentrations, when exogenously expressed in CHO cells (PMID: 18179896, Figure 2).
CaseAddInfo: The proband may or may not be a relative of the family previously reported with the same variant in PMID: 18179896, as both appear to have received medical care in the United States.
CasePMIDs: N/A
Further, over expression of hPrp4(Pro315Leu), but not hPrp4(WT), triggered systemic deformities in wild-type zebrafish embryos with the retina primarily affected, and dramatically augmented death rates in morphant embryos, in which orthologous zebrafish prpf4 gene was silenced. We conclude that mutations of PRPF4 cause RP via haploinsufficiency and dominant-negative effects, and establish PRPF4 as a new U4/U6-U5 snRNP component associated with adRP.
ExperimentName: "Variant overexpression in zebrafish causes defects in visual function."
NonHumanModel: Danio rerio
GeneAlteration: The model animals have been subjected to microinjection of PRPF4 mRNA (either wild-type or harboring the p.Pro315Leu variant), with expression levels comparable to the endogenous gene.
ModelPhenotype: Photoreceptor layer loss on macular OCT HP:0030609, Inner retinal layer loss on macular OCT HP:0030620, Photoreceptor outer segment loss on macular OCT HP:0030610
HumanPhenotype: Constriction of peripheral visual field HP:0001133, Reduced visual acuity HP:0007663,, Decreased light- and dark-adapted electroretinogram amplitude HP:0000654. Retinal degeneration HP:0000546, Macular degeneration HP:0000608, Optic disc pallor HP:0000543, Attenuation of retinal blood vessels HP:0007843, Pigmentary retinopathy HP:0000580
ModelEvidence: The variant causes severely disrupted photoreceptors in the retina (Figure 5D), reduced rhodopsin staining (rod marker) in the IS/OS layer (Figures 5E-5J) and other deformities such as malformed brains, short trunks, cardiac edema and curved body axis, at higher levels than in the wild-type control (Figures 5B and 5C). The retinal transcripts opn1lw1, gnat2, rs1, snrpg, prph2b, gnb3, and rho were decreased in the variant-expressing zebrafish (Figure 5K), while the splicing factor transcripts prpf4, prpf3, prpf31, prpf6, prpf8, snrnp200, eftud2, and sart1 were increased (Figures 5A, 5L).
ModelVariant: This model introduced the disease-associated variant NM_001244926.2(PRPF4):c.941C>T (p.Pro314Leu) in the heterozygous state (ClinVar ID: 143057).
The ophthalmic phenotype of IFT140-related ciliopathy ranges from isolated to syndromic congenital retinal dystrophy
PMID: 26359340
Gene: IFT140
HGNC: 29077
Disease: Retinitis pigmentosa 80
MONDO: 0054708
InheritancePattern: autosomal recessive
Prevalence: The overall prevalence of Retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of Retinitis pigmentosa with a recessive mode of inheritance is estimated to be 65-85% (between 1 in 3,500 and 1 in 6,500).
Penetrance: Disease caused by biallelic IFT140 variants appears to be fully penetrant.
Localization of the Functional Domains of Human Tissue Inhibitor of Metalloproteinases-3 and the Effects of a Sorsby's Fundus Dystrophy Mutation
PMID: 9642234
Gene: TIMP3
HGNC: 11822
Disease: Sorsby fundus dystrophy (SFD), also known as Sorsby's fundus dystrophy, Sorsby pseudoinflammatory fundus dystrophy, or hemorrhagic macular dystrophy
MONDO: 0007640
InheritancePattern: Autosomal Dominant
Prevalence: Estimated at 1 in 220,000 (PMID: 28847738)
Penetrance: Fully penetrant, onset between the third and sixth decades of life
Mutations in IMPG2, Encoding Interphotoreceptor Matrix Proteoglycan 2, Cause Autosomal-Recessive Retinitis Pigmentosa
PMID: 20673862
Gene: IMPG2
HGNC: 18362
Disease: retinitis pigmentosa 56
MONDO: 0013314
InheritancePattern: semi-dominant
Prevalence: Vitelliform macular dystrophy in general is estimated to have a prevalence of 1 in 5,500 (PMID: 27120116).
Penetrance: The penetrance of the phenotype among homozygous cases appears to be complete, while heterozygous carriers of deleterious variants show incomplete penetrance and variable expressivity.
Whole exome sequencing revealed novel pathogenic variants in Vietnamese patients with FEVR
PMID: 37089697
Gene: CTNNB1
HGNC: 2514
Disease: severe intellectual disability-progressive spastic diplegia syndrome
MONDO: 0014035
InheritancePattern: autosomal dominant
Prevalence: The incidence is unknown but estimated to be between 1 in 30,000 and 1 in 40,000 births (PMID: 32168371).
Penetrance: The penetrance of the cognitive impairment phenotype among cases appears to be near-complete, while the exudative vitreoretinopathy phenotype reportedly has a prevalence of ~39% among affected individuals with a syndromic diagnosis.
Mutations in the RPE65 gene in patients with autosomal recessive retinitis pigmentosa
PMID: 9501220
Gene: RPE65
HGNC: 10294
Disease: Retinitis pigmentosa 20
MONDO: 0013425
InheritancePattern: Autosomal Recessive
Prevalence: The overall prevalence of Retinitis pigmentosa is between 1 in 3,000 and 1 in 4,000 individuals, while the proportion of recessive Retinitis pigmentosa caused by RPE65 variants is ~2%. (PMID: 9501220) Thus, the prevalence of Retinitis pigmentosa 20 is between 1 in 150,000 and 1 in 200,000.
Penetrance: Fully penetrant, with onset typically in childhood
Retinal degeneration slow (rds) is a retinal disorder of an inbred strain of mice in which the outer segment of the photoreceptor cell fails to develop.
ExperimentName: The rds mouse harbors loss-of-function variants in the Prph2 gene.
NonHumanModel: Mus musculus
GeneAlteration: The model animals are homozygous for a loss-of-function variant in the Prph2 locus known as retinal degeneration slow (rds). The causal variant appears to encode a p.Gln340Pro missense change that results in the inability to detect the Prph2 protein by antibody.
ModelPhenotype: HP:0000546 (Retinal degeneration), HP:0030610 (Photoreceptor outer segment loss on macular OCT)
HumanPhenotype: HP:0030643 (Vitelliform-like retinal lesions), HP:0000533 (Chorioretinal atrophy), HP:0001105 (Retinal atrophy), HP:0007663 (Reduced visual acuity), HP:0000580 (Pigmentary retinopathy), HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0008275 (Abnormal light-adapted electroretinogram), HP:0007843 (Attenuation of retinal blood vessels), HP:0011506 (Choroidal neovascularization), HP:0030499 (Macular drusen)
ModelEvidence: This is a naturally occurring mouse model with homozygous disruption of the Prph2 locus. Phenotypes include progressive degeneration of retina, absence of rods at age 7-10 months, and reduction of the number of rows of photosensitive cell nuclei to only 1-4 rows (described in previous publications PMID: 705766 and PMID: 419532). Other previous publications have reported that the mice exhibit abnormal development of photoreceptor outer segments, as well as subsequent gradual photoreceptor degeneration of photoreceptors that is complete by age 1 year (PMID: 2918924).
ModelVariant: This model did not introduce a disease-associated variant known from an affected human patient, but rather studied a naturally occurring p.Gln340Pro missense variant disrupting the Prph2 locus.
Molecular genetic and clinical evaluation of three Chinese families with X-linked ocular albinism
PMID: 28211458
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
Autosomal Recessive Familial Exudative Vitreoretinopathy Is Associated with Mutations in LRP5
PMID: 15346351
Gene: LRP5
HGNC: 6697
Disease: osteoporosis-pseudoglioma syndrome
MONDO: 0009820
InheritancePattern: autosomal recessive
Prevalence: osteoporosis-pseudoglioma syndrome is estimated to occur in 1 out of every 2,000,000 live births.
Penetrance: The penetrance of the phenotype among homozygous or compound heterozygous cases appears to be complete, while heterozygous carriers of deleterious variants appear to be mildly affected.
R838C
Case#: Kelsell_1998_CORD6_Family_2_Proband, female, age 45 at time of report, nationality listed as British
CasePresentingHPOs: HP:0007401 (Macular atrophy), HP:0000548 (Cone/cone-rod dystrophy)
CaseHPOFreeText: N/A
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
CaseMethod1: Sanger sequencing of PCR products from each of the 18 exons of the GUCY2D locus
CaseMethod2: HhaI restriction digest of the PCR-amplified exon 13
CaseGenotypingMethod: The proband and her family members were subjected to sequencing of PCR products from each of the 18 exons of the GUCY2D locus. The PCR-amplified product from exon 13 was then subjected to HhaI restriction digest and resolved by agarose gel electrophoresis.
Variant: The proband harbors the NM_000180.4(GUCY2D):c.2512C>T (p.Arg838Cys) variant in the heterozygous state.
ClinVar: 9355
gnomAD: The variant is present in gnomAD at a frequency of 0.000007744 (1/129124) in the European non-Finnish population, with no homozygotes. https://gnomad.broadinstitute.org/variant/17-7918018-C-T
VariantEvidence: NM_000180.4(GUCY2D):c.2512C>T (p.Arg838Cys) is a missense variant located within the coiled-coil domain that mediates GUCY2D dimerization. Codon 838 has proven to be a hot spot disrupted in other families similarly affected with autosomal dominant cone-rod dystrophy (PMID: 11115851, PMID: 12552567, PMID: 26298565). The p.Arg838Cys substitution has been shown to disrupt the calcium sensitivity of GUCY2D and to trigger the inability to inactivate cyclase activity at high physiological calcium ion concentrations (PMID: 11115851).
CaseAddInfo: N/A
CasePMIDs: N/A
The RPE and photoreceptors in Timp3 mutant mice degenerated at low doses of sodium iodate, which had no effect in wildtype control mice. These studies suggest that TIMP3 mutations may result in a dysregulation of pro-oxidant—antioxidant homeostasis in the RPE, leading to RPE degeneration in SFD.
ExperimentName: Oxidative stress sensitivity in the homozygous Timp3Ser179Cys Knock-In Mouse
NonHumanModel: Mus musculus (C57Bl/6J background)
GeneAlteration: The gene alteration was constructed in a previous paper (PMID:12147610), in which the mouse Timp3 ortholog was subjected to site-directed mutagenesis to introduce a change equivalent to the human variant encoding the Ser179Cys substitution associated with Sorsby Fundus Dystrophy (PMID:8634721). This variant was introduced into embryonic stem cells by homologous recombination, generating animals for germline transmission of the Timp3Ser179Cys knock-in allele of interest.
ModelPhenotype: HP:0000580 (Pigmentary retinopathy), HP:0007703 (Abnormality of retinal pigmentation)
HumanPhenotype: HP:0007703 (Abnormality of retinal pigmentation)
ModelEvidence: The phenotypes of this model system recapitulate some of the degenerative features of the human model. Sensitivity to oxidative stress was revealed when low-dose sodium iodate triggered RPE degeneration and disorganization in the Timp3 S179C/S179C mice but not the wild-type controls (Figure 4). Rhodamine-phalloidin staining also exhibited an increased area of degeneration in the central region of the RPE in mutant mice but not in the wild-type controls (Figure 5). It is important to point out the caveat that the mice were homozygous for Timp3 Ser179Cys, whereas human patients are heterozygous. This difference in genotype introduces the possibility of loss-of-function effects that are specific to the mouse but absent from the human patients.
ModelVariant: The model variant is a knock-in modification to the mouse Timp3 ortholog that is equivalent to the human NM_000362.5(TIMP3):c.536C>G, (p.Ser179Cys) missense variant (ClinVar:12678).
II.1
Case: Gliem_2000_Family_1_patient_II.1, female, country of origin Germany, onset at 47 years of age
DiseaseAssertion: Sorsby's fundus dystrophy
FamilyInfo: The variant was inherited by the proband rather than acquired de novo.
CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0007663 (Reduced visual acuity), HP:0011510 (Drusen), HP:0000533 (Chorioretinal atrophy)
CaseHPOFreeText: Presentation at age 47 with nyctalopia. Evaluation at age 61 showed drusen deposits in macular area, near optic disk and along vascular arcades, central and midperipheral atrophy, and reduced choroidal thickness.
CaseNOTHPOs: HP:0011506 (Choroidal neovascularization)
CaseNOTHPOFreeText: N/A
CasePreviousTesting: Phenotypic characterization only
GenotypingMethod: Sanger sequencing of PCR products from all 5 exons and flanking splice junctions of the TIMP3 gene.
PreviouslyPublished: N/A
SupplementalData: N/A
Variant: Proband harbors the NM_000362.5(TIMP3):c.530A>G (p.Tyr177Cys) missense variant.
CAID: CA411540328
gnomAD: Variant is absent from gnomAD.
VariantEvidence: This missense variant within exon 5 of TIMP3 results in an unpaired Cys residue.
Evidence for a Retroviral Insertion in TRPM1 as the Cause of Congenital Stationary Night Blindness and Leopard Complex Spotting in the Horse
PMID: 24167615
Gene: TRPM1
HGNC: 7146
Disease: congenital stationary night blindness 1C
MONDO: MONDO:0013183
InheritancePattern: autosomal recessive
Prevalence: Congenital stationary night blindness has an estimated prevalence between 1 in 6,000 (PMID: 31427709) and 1 in 300,000 (PMID: 3487908). However, the prevalence of congenital stationary night blindness 1C specifically is unknown.
Penetrance: Penetrance is thought to be complete.
Previous gene expression analyses [17] did not detect expression of TRPM1 in the skin and retina of LP/LP CSNB individuals, suggesting that transcription of this gene was disrupted. However, when comparing raw read counts, we identified novel expression within intron 1, having 85 reads in the skin and 460 reads in the retina of the LP/LP horse compared to 0 and 4 reads (in the skin and retina respectively) of the lp/lp horse (Figure 3). De novo assembly of this transcript followed by PCR and genomic DNA sequencing identified a 1378 bp insertion in intron 1 (ECA1g. 108,297,929_108,297,930 ins1378) of TRPM1. In order to characterize this insertion we performed a blast analysis using RepeatMasker [27] (Figure S2). This insertion is a long terminal repeat (LTR) of an endogenous retrovirus (ERV) class II retro-element and is characterized by flanking regions of micro-homology, indicative of non-homologous end joining double stranded break repair as the mechanism of insertion (Figure 4A and Figure S2). Detection of this insertion by allele specific PCR confirmed complete association with the LP genotype (as predicted by phenotype) in tests of 511 horses (χ2=1022.00, p<<0.0005) and CSNB status in tests of 43 horses (χ2=43, p<<0.0005) (Table 2).
ExperimentName: Horse model of TRPM1 loss-of-function
NonHumanModel: Equus ferus caballus
GeneAlteration: The horse has homozygous disruption of the TRPM1 gene by a naturally occurring insertion of a 1378 bp transposon in intron 1 (g. 108,297,929_108,297,930 ins1378). A previous publication by the same group has shown that TRPM1 expression is absent from the skin and retina of these horses (PMID: 18660533).
ModelPhenotype: HP:0001053 (Hypopigmented skin patches), HP:0000591 (Abnormal sclera morphology), HP:0000662 (Nyctalopia), HP:0007984 (Electronegative electroretinogram),
HumanPhenotype: HP:0000662 (Nyctalopia), HP:0000545 (Myopia), HP:0000572 (Visual loss), HP:0007984 (Electronegative electroretinogram), HP:0000958 (Dry skin), HP:0000964 (Eczema)
ModelEvidence: The affected horses exhibit night blindness and abnormal dark-adapted ERG with absent b-wave and increased amplitude of a-wave (Figure 1). Both phenotypes are similar to the affected human patients. Melanocyte dysfunction is also shown by unpigmented areas of the skin (Figures 1 and 2) and the sclera of the eye (Figure 2A). These pigment phenotypes do not have a human equivalent, although some affected patients have been reported to have dry skin or a history of eczema (PMID: 19878917).
ModelVariant: The model harbors a naturally occurring variant that does not have an equivalent / orthologous variant reported in human patients.
Mutations in the Cone Photoreceptor G-Protein α-Subunit Gene GNAT2 in Patients with Achromatopsia
PMID: 12077706
GeneName: GNAT2
HGNC: 4394
Disease: achromatopsia 4
MonDO ID: MONDO_0013465
Inheritance: autosomal recessive
RPGR is mutated in patients with a complex X linked phenotype combining primary ciliary dyskinesia and retinitis pigmentosa
PMID: 16055928
Gene: RPGR
HGNC: 10295
Disease: RPGR-related retinopathy
MONDO: MONDO:0100437
InheritancePattern: X-linked
Prevalence: The prevalence of RPGR-related retinopathy is calculated to be approximately 1 in 214,000, based on the known incidence of retinitis pigmentosa at 1 in 3,000, the proportion of retinitis pigmentposa that is X-linked at 20%, and the proportion of X-linked retinitis pigmentosa that is RPGR-associated at 70% (PMID: 34985506).
Penetrance: Penetrance is nearly 100% in hemizygous males but is incomplete and dependent upon the variant in heterozygous female carriers.
The Y141C knockin mutation in RDS leads to complex phenotypes in the mouse
PMID: 25001182
Gene: PRPH2
HGNC: 9942
Disease: retinitis pigmentosa 7
MONDO: 0011974
InheritancePattern: semi-dominant
Prevalence: The incidence of PRPH2-related cases among inherited retinal dystrophies is reported to range from 3.5% in North America to 10.3% in France (PMID: 36010202).
Penetrance: The penetrance among biallelic cases appears to be complete, while the monoallelic cases exhibit incomplete penetrance (PMID: 36609934).
We demonstrated that TIMP3 deficiency in the mouse causes a distinct choroidal, but not retinal, phenotype characterized by prominently enlarged choroidal blood vessels. Thus, this study provides the first in vivo evidence in support of the hypothesized role of TIMP3 in the regulation of choroidal vascularization of the retina.
ExperimentName: Phenotypic characterization of the homozygous Timp3-/- Knock-Out Mouse
NonHumanModel: Mus musculus (C57/Bl6 or CD1 background)
GeneAlteration: A neomycin resistance expression cassette was cloned into plasmid-borne exon 3 of mouse Timp3. The linearized construct was transfected into embryonic stem cells and injected into blastocysts. Animals that had undergone homologous recombination were identified by locus-specific genomic PCR reactions. Predicted loss of Timp3 due to a premature stop codon and nonfunctional mRNA was confirmed at the protein level.
ModelPhenotype: HP:0030605 (Abnormal indocyanine green angiography), HP:0025568 (Abnormal morphology of the choroidal vasculature), HP:0030979 (Dilatation of large choroidal vessels)
HumanPhenotype: HP:0011506 (Choroidal neovascularization)
ModelEvidence: The model showed dilatation of the large choroid vessels, which appeared large and hyperfluorescent during ICG angiography, with balloon-like spots (Figure 3A-3B). While wild-type controls exhibited normal choroidal blood vessel network, Timp3-/- animals had abnormal vessel formations that were strongly dilated or fused (Figures 3C-3H). During in situ zymography, higher local fluorescence intensity indicated increased MMP2 and MMP9 activity in the knockout animals, as expected. Aortic explants from knockout mice showed higher spontaneous microvessel outgrowth than their counterparts from wild-type mice (Figure 6). Rescue assays suggest that the antiangiogenic activity requires the C-terminal region of TIMP3 (Figure 7).
ModelVariant: N/A (Timp3 knockout)
Generation of Bbs1M390R/M390R Knockin Mice. We targeted the Bbs1 gene in mice by constructing a vector containing regions of the mouse Bbs1 gene that replaced the normal methionine codon at position 390 in exon 12 with an arginine codon on homologous recombination (Fig. 1A). RT-PCR of cDNA amplified from the knockin mice confirmed that the M390R allele was spliced correctly without inclusion of the intronic neomycin cassette. Sequencing of the Bbs1M390R/M390R cDNA confirmed that the Bbs1 gene was modified with the incorporation of the homozygous methionine to arginine (ATG to AGG) change in the knockin line (Fig. 1B).
ExperimentName: Knock-in of the p.M390R variant into the mouse Bbs1 gene.
NonHumanModel: Mus musculus
GeneAlteration: The model animals have been subjected to homologous recombination-based knock-in of the p.M390R variant into exon 12 of the endogenous mouse Bbs1 gene. The variant has been studied in the homozygous state.
ModelPhenotype: HP:0032558 (Absent sperm flagella), HP:0010633 (Partial anosmia), HP:0012433 (Abnormal social behavior), HP:0030469 (Abnormal dark-adapted electroretinogram), HP:0030610 (Photoreceptor outer segment loss on macular OCT), HP:0030609 (Photoreceptor layer loss on macular OCT), HP:0001513 (Obesity), HP:0002119 (Ventriculomegaly),
HumanPhenotype: HP:0000639 (Nystagmus), HP:0000510 (Rod-cone dystrophy), HP:0007663 (Reduced visual acuity), HP:0000662 (Nyctalopia), HP:0000518 (Cataract), HP:0008323 (Abnormal light- and dark-adapted electroretinogram), HP:0000107 (Renal cyst), HP:0001513 (Obesity), HP:0010442 (Polydactyly), HP:0002463 (Language impairment), HP:0000026 (Male hypogonadism)
ModelEvidence: Sperm flagella were absent (Figures 2A, 2B). Loss of the outer nuclear layer and degeneration of the photoreceptor inner and outer segments were observed in older mice (Figures 2C, 2D). Photoreceptor morphology in the outer segment was also disrupted in TEM images (Figure 2E). Scotopic responses showed a- and b-wave attenuation (Figure 2G), while photopic responses were not significantly different (Figure 2H). Homozygous mice showed obesity relative to wild-type and heterozygous mice (Figure 3). Brain sections showed neuroanatomical defects, especially ventriculomegaly (Figure 4). Brain cilia were morphologically abnormal (Figure 5). Renal cysts and polydactyly were investigated but not observed.
ModelVariant: This model introduced a disease-associated variant known from affected human patients (NM_024649.5(BBS1):c.1169T>G (p.Met390Arg), ClinVar ID: 12143).
OA1 mutations and deletions in X-linked ocular albinism.
PMID: 9529334
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
We also found reduced photoreceptor responses in Adam9 knockout mice, previously reported to be asymptomatic. In 12-month-old knockout mice, photoreceptors appear normal, but the apical processes of the retinal pigment epithelium (RPE) cells are disorganized and contact between photoreceptor outer segments (POSs) and the RPE apical surface is compromised. In 20-month-old mice, there is clear evidence of progressive retinal degeneration with disorganized POS and thinning of the outer nuclear layer (ONL) in addition to the anomaly at the POS-RPE junction. RPE basal deposits and macrophages were also apparent in older mice.
ExperimentName: Mouse model of Adam9 loss-of-function
NonHumanModel: Mus musculus
GeneAlteration: The mice harbor homozygous knockout of the Adam9 gene by an insertion of a neomycin selection cassette in to the exon encoding amino acids 32 to 66 of Adam9 (PMID: 11839819).
ModelPhenotype: HP:0000546 (Retinal degeneration), HP:0007703 (Abnormality of retinal pigmentation), HP:0030610 (Photoreceptor outer segment loss on macular OCT), HP:0030483 (Reduced amplitude of dark-adapted bright flash electroretinogram a-wave), HP:0007984 (Electronegative electroretinogram), HP:0008323 (Abnormal light- and dark-adapted electroretinogram)
HumanPhenotype: HP:0410280 (Pediatric onset), HP:0007663 (Reduced visual acuity), HP:0007401 (Macular atrophy), HP:0000580 (Pigmentary retinopathy), HP:0007769 (Peripheral retinal degeneration), HP:0008323 (Abnormal light- and dark-adapted electroretinogram), HP:0000548 (Cone/cone-rod dystrophy), HP:0007994 (Peripheral visual field loss), HP:0000545 (Myopia)
ModelEvidence: The affected mice exhibit an abnormal gap between the RPE and the photoreceptor outer segment, which would normally be in contact (Figure 5B). The gap contains macrophages (Figure 5L). Outer nuclear layer thinning is observed (Figure 5D), as well as material deposited between the RPE and Bruch's membrane, which may be analogous to drusen deposits in humans (Figure 5K). These findings collectively show an adhesion defect at the interface between the photoreceptor outer segment and the RPE. This evidence of retinal degeneration was complemented by abnormalities in both rod- and cone-driven ERG responses (Figure 4), matching a feature of the human patients.
ModelVariant: The model harbors a targeted disruption that does not have an equivalent / orthologous variant reported in human patients.
patients
Case#: Olivier_2021_Family_K_Proband_II:3, male, age 43 years at the time of onset, national origin reported as Spanish
CasePresentingHPOs: HP:0000662 (Nyctalopia), HP:0001099 (Fundus atrophy), HP:0007737 (Bone spicule pigmentation of the retina)
CaseHPOFreeText: The proband has onset of retinitis pigmentosa at the age of 43 years.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: It is not clear whether previous testing methods included systematic genotyping of loci associated with VMD or RP.
CaseMethod1: Screening of IMPG1 using either gene panel testing or exome sequencing
CaseMethod2: Sanger sequencing-based confirmation
CaseGenotypingMethod: Genotyping is not entirely clear but has at least included panel-based analysis of the IMPG1 locus and Sanger sequencing-based confirmation.
Variant: The proband harbors the NM_001563.4(IMPG1):c.1982G>A (p.Arg661His) variant in the homozygous state.
ClinVar ID: 1056230
gnomAD: The NM_001563.4(IMPG1):c.1982G>A (p.Arg661His) variant is found in gnomAD v2.1.1 at a frequency of 0.00004006 (1/24964) in the African / African-American population, with 0 homozygotes https://gnomad.broadinstitute.org/variant/6-76657093-C-T
VariantEvidence: NM_001563.4(IMPG1):c.1982G>A (p.Arg661His) is a missense variant, which does not have experimental evidence of a functional effect on the protein product.
CaseAddInfo: The patient's affected sister shares the same homozygous genotype.
CasePMIDs: N/A
RP
Case#: Olivier_2021_Family_H_Proband_II:1, male, age 53 years at the time of diagnosis, national origin reported as French
CasePresentingHPOs: HP:0007401 (Macular atrophy), HP:0007737 (Bone spicule pigmentation of the retina)
CaseHPOFreeText: The proband has been diagnosed with maculopathy at the age of 53 years, and exhibits retinal discoloration.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: It is not clear whether previous testing methods included systematic genotyping of loci associated with VMD or RP.
CaseMethod1: Screening of IMPG1 using either gene panel testing or exome sequencing
CaseMethod2: Sanger sequencing-based confirmation
CaseGenotypingMethod: Genotyping is not entirely clear but has at least included panel-based analysis of the IMPG1 locus and Sanger sequencing-based confirmation.
Variant: The proband harbors the NM_001563.4:c.2083G>T (p.Glu695Ter) variant in the heterozygous state.
CAID: CA364770054
gnomAD: This variant is not found in gnomAD v2.1.1.
VariantEvidence: NM_001563.4:c.2083G>T (p.Glu695Ter) is a nonsense variant in exon 15 of 17, which is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 13% of the protein product.
CaseAddInfo: The patient's brother is an unaffected carrier of the variant.
CasePMIDs: N/A
Combined NGS Approaches Identify Mutations in the Intraflagellar Transport Gene IFT140 in Skeletal Ciliopathies with Early Progressive Kidney Disease
PMID: 23418020
Gene: IFT140
HGNC: 29077
Disease: short-rib thoracic dysplasia 9 with or without polydactyly
MONDO: 0009964
InheritancePattern: Autosomal Recessive
Prevalence: The overall prevalence of short-rib thoracic dysplasia is estimated to be between 1 in 100,000 and 1 in 130,000 births (PMID: 931421).
Penetrance: Disease caused by biallelic IFT140 variants appears to be fully penetrant.
Mutations in GPR143/OA1 and ABCA4 Inform Interpretations of Short-Wavelength and Near-Infrared Fundus Autofluorescence
PMID: 29847651
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.