Molecular and clinical characterization of a pedigree with factor XI deficiency, including a novel missense variant (p.Cys200Phe): a case report.

Abstract

Introduction: Coagulation factor XI (FXI) deficiency is a rare bleeding disorder, we aimed to identify potential variants of F11 gene in a pedigree with hereditary FXI deficiency and explore the molecular pathogenesis.

Case presentation: A pedigree with FXI deficiency was included in this study. The proband was an 80-year-old Asian woman who showed a significantly prolonged activated partial thromboplastin time (APTT), along with markedly decreased FXI activity and antigen levels. Direct DNA sequencing of all F11 gene exons identified compound heterozygous variants (p.Trp246* and p.Cys200Phe) in the proband. The daughter was heterozygous for p.Cys200Phe, who had an FXI coagulant activity (FXI: C) of 41.0% and FXI antigen level (FXI: Ag) of 48.0%. Her son and elder granddaughter were heterozygous for p.Trp246*, presenting FXI: C of 35.0% and 34.2%, and FXI: Ag of 43.3% and 53.0%, respectively. Bioinformatics analysis and protein modeling demonstrated that both variants were likely pathogenic, impairing the structure and function of the FXI protein and contributing to FXI deficiency in this pedigree.

Conclusion: In summary, we identified compound heterozygous variants (p.Trp246* and p.Cys200Phe) as the likely genetic cause of FXI deficiency in this family. The missense variant p.Cys200Phe has not been reported previously. This study expands the genotypic spectrum of the F11 gene, which is beneficial for enhancing the accuracy of molecular diagnosis, optimizing clinical risk assessment, and facilitating individualized clinical management and genetic counseling for patients with FXI deficiency.