A novel compound heterozygous variant linked to hematuria in a family with hereditary factor VII deficiency

Background Hereditary factor VII deficiency (FVIID) is a rare congenital autosomal recessive bleeding disorder. In clinical manifestations, its onset is caused by variant of the F7 gene (NM_019616) with strong heterogeneity. We identified a family with hematuria caused by a novel F7 compound heterozygous variant and investigated the FVIID‐dependent mechanism impacted by these variants. Methods Coagulation factors in the proband were functionally verified. We located pathogenic variants in relevant genes using next‐generation sequencing after target enrichment and verified them by Sanger sequencing. We examined the coagulation activity and secretion pattern of recombinant FVII variants expressed in cells and observed their location and stability by immunofluorescence. Results We found a missense variant c.1207G>A (p.Gly403Ser) and a frameshift variant c.154_155del (p.Arg53fs) in the F7 gene of the proband. FVII activity tests showed that the variants significantly decreased its presence in the cell culture supernatant. Moreover, the R53fs mutant lacked the FVII functional domain and had no detectable activity. Immunofluorescence indicated that the p.Gly403Ser variant was distributed to the cell membrane and cytoplasm, whereas the FVII R53fs variant was not detected. Deficient FVII protein function and severe coagulation disorder are the likely causes of hematuria and other bleeding symptoms in the proband. Conclusions The newly discovered F7 gene variants enrich the spectrum of hereditary FVII deficiency and provide a new foundation for the diagnosis and treatment of this type of coagulation disorder. A cell model about wild‐type and mutant F7 protein is reported. The wild‐type F7 protein could be effectively translated and secreted via vesicular transport (left). The p.G403S mutant coded by c.1207G>A was detained and degraded in the cell cytoplasm, causing reduced secretion of F7 mutant (middle). The p.R53fs truncated mutant coded by c.154_155del lost active domain and was expressed decreasingly (right).