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Congenital factor V deficiency, also known as parahaemophilia, is a rare autosomal recessive coagulopathy affecting approximately 1 in 1,000,000 individuals (PMID:23881482; PMID:40421928). Affected patients present in early childhood with mucocutaneous bleeding, menorrhagia, or life-threatening hemorrhage, often discovered upon surgical hemostatic challenges. Laboratory evaluation shows markedly prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT) that corrects on mixing studies. Plasma factor V activity and antigen levels span undetectable to 48% of normal in a cohort of 45 patients from the Chinese National Haemophilia Registry (PMID:40421928). The disorder exhibits variable clinical expressivity, with poor genotype-phenotype correlation necessitating molecular diagnosis. Fresh frozen plasma remains the mainstay of treatment.
F5-related deficiency follows autosomal recessive inheritance, with homozygous or compound heterozygous variants in the F5 gene (PMID:32000417). Clinically significant bleeding is observed when FV activity falls below 10%, whereas heterozygous carriers are asymptomatic or have mild prolongation of clotting times. In Indian and African American patients, multiple novel small deletions and splice site mutations have been identified, emphasizing ethnic heterogeneity (PMID:17145618; PMID:33769317). Twin studies demonstrate concordant phenotypes in siblings inheriting distinct paternal and maternal missense variants (PMID:34387626). Carrier testing in parents reveals 50% FV activity in heterozygous individuals without bleeding tendencies. Genetic counselling is essential for at-risk families.
Genetic evidence comprises over 65 unrelated probands harboring diverse variant classes, including missense, frameshift, nonsense, and splice site mutations (PMID:40421928; PMID:17145618). For example, the frameshift variant c.2426del (p.Pro809HisfsTer2) has been reported in a 52-year-old patient with 7% FV activity (PMID:32000417). Additional alleles include c.2439del (p.Ile814LeufsTer23) in a 13-year-old patient misdiagnosed as an abscess (PMID:39560563). Recurrent founder variants in Chinese and Indian cohorts further define population-specific alleles (PMID:31789663; PMID:17145618). The broad variant spectrum solidifies the strong genetic evidence for F5 in this disorder.
Segregation analyses in at least 15 families demonstrate co-segregation of biallelic F5 variants with FV deficiency in 19 affected relatives (PMID:34387626; PMID:9576178). In the British family with a 4 bp deletion, the homozygous child exhibited undetectable FV levels, while both parents were asymptomatic heterozygotes (PMID:9576178). The twin study confirmed compound heterozygosity with paternal c.5113A>C (p.Ser1705Arg) and maternal c.4949C>T (p.Ala1650Val) variants in both siblings (PMID:34387626). Multicenter cohorts consistently show autosomal recessive segregation patterns. Overall, genetic data meet the ClinGen strong tier and reach the maximum genetic scoring cap.
Functional studies elucidate haploinsufficiency as the primary disease mechanism. The His147Arg missense mutation in the A1 domain was shown to disrupt FVa stability and reduce cofactor activity to 63.5% upon in vitro expression in COS-1 cells, despite normal antigen levels (PMID:24787990). Splice site mutation c.6529-1G>T abolishes canonical acceptor site usage, leading to truncated transcript and correlating with 3% FV activity (PMID:33769317). Nonsense variants, such as p.Gln2031Ter, produce unstable proteins with reduced secretion in expression assays (PMID:24675695). Frameshift alleles like c.3924_3927del (p.Ser1308fs) result in premature stop codons and undetectable heavy chains in patient plasma (PMID:9576178). These concordant functional data provide moderate experimental support for variant pathogenicity.
No studies dispute the association of F5 loss-of-function variants with congenital factor V deficiency. Cumulatively, the case reports, familial segregation, and functional assays support a Definitive gene-disease relationship. Genetic testing via targeted sequencing is recommended for confirmatory diagnosis and carrier detection. Understanding variant-specific functional impacts may inform tailored management and prognostic counseling. Additional research on genotype-phenotype correlations could refine variant interpretation. Key Take-home: F5 loss-of-function variants cause autosomal recessive congenital factor V deficiency, with high clinical utility for genetic diagnosis and management.
Gene–Disease AssociationDefinitive
Genetic EvidenceStrong65 unrelated probands with diverse biallelic F5 variants; segregation in 19 affected relatives in at least 15 families Functional EvidenceModerateMultiple in vitro expression and functional assays demonstrating impaired FVa stability and secretion |