Gene Validity Curation

F8 - hemophilia A

Gene: F8 (HGNC:3546)
Classification - 07/24/2019
Disease: hemophilia A (MONDO_0010602)
Mode of Inheritance: X-linked inheritance (HP:0001417)
Replication over time: YES Contradictory Evidence: NO
Expert Panel: Hemostasis Thrombosis EP
Evidence Summary: F8 was reported in relation to X-linked Hemophilia A as early as 1985 (Gitschier et al., PMID: 2987704). More than 1000 pathogenic variants in this gene are reported in humans, ranging from whole gene deletions, partial deletions and duplications, nonsense, frameshift and splicing variants to a number of functionally-characterized missense variants. Hemophilia A is characterized by severe bleeding diagnosed by an increased bleeding time, reduced Factor VIII activity and antigen levels. Spontaneous bleeding into joints and soft tissues is often reported. Summary of Case Level Data (12 points): Variants in this gene are reported in at least 14 probands in 8 publications (PMIDs: 2987704, 30210749, 3035554, 10886198, 8281136, 2105106, 16805874, 28252515). Variants in this gene segregated with disease in 10 additional family members. More case-level evidence is available in the literature, but the maximum score for genetic evidence has been reached. The mechanism for disease is hemizygous loss of function in males, with the majority of variants observed resulting in undetectable FVIII activity (PMID: 2987704). Homozygous loss of function is reported in some female patients with severe bleeding diathesis, while most females are heterozygous carriers. A proportion of patients with null variants are reported to develop antibodies to recombinant FVIII. (PMIDs: 24498605, 22102273, 20081061, 19336737). Summary of Experimental Data (4.5 points): FVIII is involved in the blood coagulation pathway and functions to activate FX by forming the tenase complex with FIX (PMID: 3286010). Hemophilia A has been studied in dogs since 1950 (PMID: 15431070, 24253479, 22137432), while horse (PMID: 6838443) and mouse models (PMID: 7647782, 24705491) also have been used extensively in Hemophilia research. These animal models have been helpful in the development of recombinant FVIII for treatment of Hemophilia A. The F8 gene disruption results in loss of function and absence of detectable FVIII:C in mice with a phenotype of severe bleeding. This is shown to be rescued by RNA trans-splicing to yield a full-length, wild-type protein in FVIII-deficient mice. Gene therapy in humans for Hemophilia A using recombinant adeno-associated virus (rAAV)–mediated gene transfer is at the clinical trials stage. In summary, the F8-Hemophilia A gene-disease relationship is Definitive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.
Genetic Evidence
Case-Level Data
Evidence Type Case Information Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Variant Evidence
Autosomal Dominant or X-linked Disorder Variant is de novo 2 0-3 12 2
4
4
Gitschier J et al. 1985 May 30-Jun 5 (PMID:2987704); Casula L et al. 1990 Feb 1 (PMID:2105106);
Proband with predicted or proven null variant 1.5 0-2 10 5 7.5 7.5
Zahari M et al. 2018 Sep 1 (PMID:30210749); Youssoufian H et al. 1987 Jun (PMID:3035554); Cai XH et al. 2006 Sep (PMID:16805874); Bai N et al. 2017 Oct (PMID:28252515);
Proband with other variant type with some evidence of gene impact 0.5 0-1.5 7 2
1.5
1.5
Naylor J et al. 1993 Nov (PMID:8281136); Schwaab R et al. 2000 Jun (PMID:10886198);
Autosomal Recessive Disease Two variants in trans and at least one de novo or a predicted/proven null variant 2 0-3 12
Two variants (not predicted/proven null) with some evidence of gene impact in trans 1 0-1.5
Segregation Evidence   Summed LOD Family Count 1 1  
Candidate gene sequencing 3.01 1
Schwaab R et al. 2000 Jun (PMID:10886198);
Exome/genome or all genes sequenced in linkage region
Total Summed LOD Score 3.01    
Case-Control Data
Case-Control Study Type Case-Control Quality Criteria Guidelines Points PMIDs/Notes
Points/Study Max Count Points Counted
Single Variant Analysis 1. Variant Detection Methodology
2. Power
3. Bias and confounding
4. Statistical Significance
0-6 12
Aggregate Variant Analysis 0-6
Total Genetic Evidence Points (Maximum 12) 12
Experimental Evidence
Evidence Category Evidence Type Guidelines Points PMIDs/Notes
Default Range Max Count Total Counted
Function Biochemical Function 0.5 0 - 2 2 1
0.5
0.5
Furie B et al. 1988 May 20 (PMID:3286010);
Protein Interaction 0.5 0 - 2
Expression 0.5 0 - 2
Functional Alteration Patient cells 1 0 - 2 2
Non-patient cells 0.5 0 - 1
Models Non-human model organism 2 0 - 4 4 1 2 4
Bi L et al. 1995 May (PMID:7647782);
Cell culture model 1 0 - 2
Rescue Rescue in human 2 0 - 4
Rescue in non-human model organism 2 0 - 4 1
2
Chao H et al. 2003 Aug (PMID:12847523);
Rescue in cell culture model 1 0 - 2
Rescue in patient cells 1 0 - 2
Total Experimental Evidence Points (Maximum 6) 4.5

 


 

Assertion criteria Genetic Evidence (0-12 points) Experimental Evidence
(0-6 points)
Total Points
(0-18)
Replication Over Time (Y/N)
Description Case-level, family segregation, or case-control data that support the gene-disease association Gene-level experimental evidence that support the gene-disease association Sum of Genetic & Experimental
Evidence
> 2 pubs w/ convincing evidence over time (>3 yrs)
Assigned Points 12 4.5 16.5 YES
CALCULATED CLASSIFICATION LIMITED 1-6
MODERATE 7-11
STRONG 12-18
DEFINITIVE 12-18 AND replication over time
Valid contradictory evidence (Y/N)*
NO
CALCULATED CLASSIFICATION (DATE)
Definitive
07/15/2019
EXPERT CURATION (DATE)
Definitive
07/24/2019
EVIDENCE SUMMARY
F8 was reported in relation to X-linked Hemophilia A as early as 1985 (Gitschier et al., PMID: 2987704). More than 1000 pathogenic variants in this gene are reported in humans, ranging from whole gene deletions, partial deletions and duplications, nonsense, frameshift and splicing variants to a number of functionally-characterized missense variants. Hemophilia A is characterized by severe bleeding diagnosed by an increased bleeding time, reduced Factor VIII activity and antigen levels. Spontaneous bleeding into joints and soft tissues is often reported. Summary of Case Level Data (12 points): Variants in this gene are reported in at least 14 probands in 8 publications (PMIDs: 2987704, 30210749, 3035554, 10886198, 8281136, 2105106, 16805874, 28252515). Variants in this gene segregated with disease in 10 additional family members. More case-level evidence is available in the literature, but the maximum score for genetic evidence has been reached. The mechanism for disease is hemizygous loss of function in males, with the majority of variants observed resulting in undetectable FVIII activity (PMID: 2987704). Homozygous loss of function is reported in some female patients with severe bleeding diathesis, while most females are heterozygous carriers. A proportion of patients with null variants are reported to develop antibodies to recombinant FVIII. (PMIDs: 24498605, 22102273, 20081061, 19336737). Summary of Experimental Data (4.5 points): FVIII is involved in the blood coagulation pathway and functions to activate FX by forming the tenase complex with FIX (PMID: 3286010). Hemophilia A has been studied in dogs since 1950 (PMID: 15431070, 24253479, 22137432), while horse (PMID: 6838443) and mouse models (PMID: 7647782, 24705491) also have been used extensively in Hemophilia research. These animal models have been helpful in the development of recombinant FVIII for treatment of Hemophilia A. The F8 gene disruption results in loss of function and absence of detectable FVIII:C in mice with a phenotype of severe bleeding. This is shown to be rescued by RNA trans-splicing to yield a full-length, wild-type protein in FVIII-deficient mice. Gene therapy in humans for Hemophilia A using recombinant adeno-associated virus (rAAV)–mediated gene transfer is at the clinical trials stage. In summary, the F8-Hemophilia A gene-disease relationship is Definitive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.