Genetic analysis of a family with inherited factor Ⅶ deficiency
Objective To analyze the clinical data of a family with inherited factor Ⅶ(FⅦ)deficiency,and to explore its genetic etiology.Methods A patient with inherited FⅦ deficiency was diagnosed in Fuwai Central China Cardiovascular Hospital on April 15,2023,and the clinical data were collected from the proband and his family members.The coagulation testing(prothrombin time,activated partial thromboplastin time,etc.)and coagulation factors activities(FⅡ∶C,F Ⅴ∶C,FⅦ∶C,FⅩ∶C)were detected.The related variants of F7 gene were detected by whole exome sequencing.The mutation sites were verified by Sanger sequencing.The conservation of mutant sites was analyzed by ClustalX2.1 software.The protein conformation changes of the mutant sites were predicted by PyMOL2.6.0 software.The pathogenicity of the mutations was evaluated by ACMG guideline.Results The prothrombin time of the proband and his brother prolonged significantly,and F Ⅶ:C was significantly reduced.His sister,son,daughter,son's son,and daughter's son had varying degrees of reduced F Ⅶ:C,while the rest of the family members had normal F Ⅶ:C.The proband had compound heterozygous mutations of c.64G＞A(p.Gly22Ser)and c.1224T＞G(p.His408Gln)in F7 gene,which resulted in the change of glycine to serine at position 22 in the leading sequence coded by exon 1,and histidine to glutamine at position 408 in the catalytic region coded by exon 9.His brother carried the same compound heterozygous mutations.His daughter and daughter's son carried the heterozygous mutation c.64G＞A(p.Gly22Ser).His sister,son and son's son carried the heterozygous mutation c.1224T＞G(p.His408Gln).The results of the other family members were wild type.Gly22 was not highly conserved in FⅦ of eight homologous species(human,red junglefowl,Xenopus tropicalis,rhesus monkey,dog,house mouse,brown rat,cow),but was highly conserved in human vitamin K-dependent coagulation factors FⅦ,FⅨ and FX.His408 was highly conserved in FⅦ of eight homologous species and in human vitamin K-dependent coagulation factors FⅦ,FⅨ and FX.F7 gene mutation sites c.64G＞A(p.Gly22Ser)and c.1224T＞G(p.His408Gln)were reported in the literature,and were very low-frequency sites in the databases such as dbSNP,1000G,ESP6500 and ExAC,with ACMG guideline rating of pathogenicity(PS1+PM2+PM3+PP3+PP4+PP5).Conclusion The compound heterozygous mutations of c.64G＞A(p.Gly22Ser)and c.1224T＞G(p.His408Gln)in F7 gene are the cause of autosomal recessive inherited FⅦ deficiency in this family,which may affect the molecular structure and function of FⅦ protein,resulting in decreased plasma FⅦ:C,with clinical manifestations of mild or no bleeding.
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