A Novel Compound Heterozygous Mutation in a Family With Hereditary Factor VII (FVII) Deficiency With Hematuria

Background: Hereditary Factor VII deficiency (FVIID) is the most common rare congenital autosomal recessive bleeding disorder and is mainly caused by F7 gene (NM_019616) mutation with strong heterogeneity in clinical manifestations. In this study, we report a family with hematuria caused by a novel FVII compound heterozygous mutation and analyze the mechanism of FVI deficiency caused by this mutation combination. Methods: We performed the functional verification of coagulation factors in blood of the proband and target enrichment for next-generation sequencing (NGS) was used to check the pathogenic mutation of relevant genes, which were further identified by Sanger sequencing. We tested coagulation activity and secretion of FVII mutants in recombinant expressed cell, and observed the location and stability of mutants by immunofluorescence. Findings: We found the inactivation missense mutation c.1207G>A (p.Gly403Ser) and frameshift mutation c.157_158del (p.Arg53fs) in the F7 gene of the patient. FVII activity tests showed that the two FVII mutants significantly decreased the activity of FVII in the supernatant of cell culture medium, even though the R53fs mutant had no detectable activity in cells due to complete deletion of the FVII functional domain. Immunofluorescence indicated that the G403S variant was scattered on the cell membrane and cytoplasm, which may cause abnormal endoplasmic reticulum retention and degradation in cells. These two mutations lead to deficient FVII protein function and severe coagulation disorder in the proband, which is the likely cause of hematuria and other bleeding symptoms. Interpretation: The detection of F7 gene is helpful to the diagnosis of FVII deficiency and its complications. The newly discovered F7 gene mutation enriches the gene mutation spectrum of FVII deficiency , and provides a new idea and basis for the diagnosis and treatment of this kind of coagulation disorder. Funding Information: The study was supported by grants from the Fujian Province Medical Innovation Foundation, Grant/Award Numbers: 2019-CXB -3, -4; National Natural Science Foundation of China, Grant/Award Numbers: 81874379. Declaration of Interest: The authors declare that they have no conflict of interest. Ethical Approval: This study was approved by the Ethics Committee of Fujian Provincial Hospital, and all investigated family members in this study signed an informed consent form.