ClinGen Dosage Sensitivity Curation Page

F8

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
  • Haploinsufficiency score: 3
  • Strength of Evidence (disclaimer): Sufficient evidence for dosage pathogenicity
  • Haploinsufficiency Phenotype: HEMOPHILIA A; HEMA
Evidence for haploinsufficiency phenotype
PubMed ID Description
2987704 Gitschier (1985) screened 92 haemophiliacs by southern blot analysis of the F8 gene using the TaqI enzyme. They identified two different stopgain mutations and two microdeletions. A de novo stopgain mutation in exon 24 of F8 (ARG2209TER) was identified by Southern blotting in a male subject (H2) with haemophilia A and no family history of disease. The stopgain mutation was confirmed by amplification and sequencing of exon 24 in this family. A maternally inherited stopgain in exon 26 of F8 (ARG2307TER) was identified in a male subject (H22) and his affected male sibling and occurs 26 amino acids upstream of the termination codon. This variant occurs in the last exon and is not predicted to result in nonsense mediated decay. Two instances of partial deletion of the F8 gene include an ~39.0 kb in-frame deletion of exons 23-25 identified in a male subject (H96), and an exon 26 deletion identified in a second male subject (H51). The breakpoints were estimated by Southern blot analysis and were not sequenced.
23534532 Rossetti (2013) genotyped 260 Argentinian haemophilia A patients using inverse shifting PCR (inversion detection), multiplex PCR (large deletions), and conformation sensitive gel electrophoresis (indels and point mutations). They identified a causative variant in 104/104 patients with severe Haemophilia A. This included 59 patients with a recurrent inversion disrupting F8 with one breakpoint positioned in intron 22 (Inv22), 12 patients with large deletions, 12 patients with nonsense mutations, 18 patients with frameshift variants, and three subjects with missense variants.
23551875 You (2013) analyzed DNA samples from 10 patients with severe haemophilia A who were presumed to carry deletions in the F8 gene due to previous failures to amplify exons by conventional PCR analysis. They used a multiplex fluorescence competitive amplification technique (AccuCopy) to detect copy number, and sequenced deletion breakpoints using PCR. The ten exonic deletions included two exon 1 deletions, three frameshift deletions (exons 2-6, exons 2-12, and exon 15), and five in-frame deletions. A DNA sample was available for the mother of a male patient (5-P) with a 27.7 kb in-frame deletion of exons 4-7, and she was confirmed to be a carrier of the deletion.

Haploinsufficiency phenotype comments:

Haemophilia A has a prevalence of approximately 1 in 5000 males. Loss-of-function variants in F8 are a known cause of this X-linked recessive disorder. Numerous deletions and loss-of-function point mutations are reported in public/commercial databases. A recurrent inversion with one breakpoint positioned in intron 22 of F8 is identified up to 50% of subjects with severe haemophilia A (see MIM:300841 and GeneReviews). Carrier females do not present with Haemophilia A, however, approximately 30% of heterozygous carrier females have clotting activity below 40% and are at risk of bleeding disorder (see GeneReviews).

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.