Five new F10 variants in hereditary factor x deficiency detected by high‐throughput sequencing

• Published in: Haemophilia : the official journal of the World Federation of Hemophilia Vol. 29; no. 6; pp. 1565 - 1572
• Main Authors: Pastoret, Cédric, Wahl, Clémentine, Castet, Sabine, Nedelec, Fabienne, Pontis, Adeline, Bayart, Sophie, Fest, Thierry, Guillet, Benoît
• Format: Journal Article
• Language: English
• Published: Chichester Wiley Subscription Services, Inc 01.11.2023; Wiley
• Subjects: Bleeding; bleeding disorder; Coagulation factors; Copy number; F10 gene; factor X deficiency; Feasibility studies; Genes; Genotypes; high throughput sequencing; Life Sciences; Light chains; Malignancy; Phenotypes; Medicine; Allele; Phenotype; Missense mutation; Gene; Nonsense mutation; Frameshift mutation; Nonsense; Genetics; Biology; Bioinformatics
• ISSN: 1351-8216; 1365-2516
• DOI: 10.1111/hae.14888

Introduction Factor X deficiency is a rare inherited bleeding disorder. To date, 181 variants are reported in the recently updated F10‐gene variant database. Aim This study aimed to describe new F10 variants. Method The F10 gene was analysed in 16 consecutive families with FX deficiency by a targeted high‐throughput sequencing approach, including F10, F9, F8 genes, and 78 genes dedicated to haematological malignancies. Results We identified 19 variants (17 missense, one nonsense and one frameshift) and two copy number variations. Two patients presenting a combined FVII‐FX deficiency showed a loss of one F10 gene copy (del13q34) associated with a missense variant on the remaining allele, leading to a FX:C significantly lower than the FVII:C level and explaining their unusual bleeding history. We reported five novel variants. Three missense variants (p.Glu22Val affecting the signal peptide cleavage site, p.Cys342Tyr removing the disulphide bond between the FX heavy and light chains, and p.Val385Met located in FX peptidase S1 domain) were detected at compound heterozygosis status in three patients with severe bleeding symptoms and FX:C level below 10 IU/dL. Two truncating variants p.Tyr279* and p.Thr434Aspfs*13 leading to an altered FX protein were found at heterozygous state in two patients with mild bleeding history. Conclusion This study showed the feasibility and the interest of high‐throughput sequencing approach for rare bleeding disorders, enabling the report of F10 gene screening in a 3‐weeks delay, suitable for clinical use. The description of five new variants may contribute to a better understanding of the phenotype‐genotype correlation in FX deficiency.