ClinGen Dosage Sensitivity Curation Page

F9

  • 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 B; HEMB
Evidence for haploinsufficiency phenotype
PubMed ID Description
20301668 Hemophilia B is an X?chromosome?linked inherited bleeding disorder primarily affecting males, but those carrier females with reduced factor IX (F9) activity levels may also experience some bleeding. Hemophilia B has a prevalence of approximately 1 in 30,000 males. Loss-of-function variants in the F9 gene are a known cause of this disorder. Numerous deletions and loss-of-function point mutations are reported in public/commercial databases (see MIM: #300746 and GeneReviews). (1/11/2021 JT)
29296726 Johnsen et al. (2017) used an NGS-based approach to genotype hemophilia patients in a large study comprising of approximately 15% of hemophilia cases in the United States and detected a causative variant in the F9 gene in 595/599 individuals with hemophilia B, including 217 previously unreported unique variants. Missense variants accounted for most of the variants detected in males with mild or moderate hemophilia B (87%). Nonsense, frameshift, and larger (>50 bp) SVs including inversions made up to 45% of variants detected in males with severe hemophilia B, consistent with the predicted negative impact of these types of variants on gene function. (1/11/2021 JT)

Haploinsufficiency phenotype comments:

Deletions and loss of function mutations in F9 result in hemophilia B in males. Deletions or duplications of exons resulting in loss of function account for 3% of all mutations. Heterozygous females are typically unaffected carriers but may have abnormal bleeding, depending on their F9 clotting activity levels. See Gene Reviews. Loss-of-function variants in F9 are a known cause of hemophilia B with deletions and loss-of-function point mutations representing the majority of cases. Pinotti (2012) demonstrated the mechanisms through which F9 nonsense mutations impair gene expression include ribosome readthrough, which consists of misrecognition of the premature stop codon by an aminoacyl-tRNA instead of the termination factors. Hemophilia patients with nonsense mutations have a lower risk of developing inhibitors than patients with larger gene deletions. F9 coagulent activity levels were determined by aPTT-based assays and F9 proteins levels by ELISA. F9 mRNA levels were detected by reverse transcription followed by RT-PCR and expression studies in HEK293 cells. Ribosome readthrough may account for minimal full-length protein biosynthesis in a small number of HB cases that are caused by the R162*, R294*, R298* mutations, which showed appreciable levels of secreted F9 protein in vitro and in vivo (PMID: 22618954). Recurring mutations commonly occur as founder mutations in some populations. Lasalle (2017) identified recurrent variant c.835G>A (p.Ala279Thr) in 34 HB patients from two different regions of France representing the largest cohort of hemophilia patients with an identical variant. Haplotype reconstruction of extragenic and intragenic polymorphic markers was performed to demonstrate a founder effect for this variant. Recurrence of the other approximately 1,000 different F9 variants was shown to remain limited (PMID: 29296726). (1/11/2021 JT)

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.