Complex Molecular Diagnostics of Hemophilia A in Russian Patients

摘要

Hemophilia A is a frequent X-linked recessive blood clotting disorder. It is caused by mutations in the F8 gene (locus Xq28) and affects 1 in 5000 newborn boys. The aim of this study was to determine the spectrum of the F8 gene mutations in the Russian patients with hemophilia A. Samples from 117 unrelated families with an incoming diagnosis of hemophilia A were tested by IS-PCR, multiplex PCR, MPS technology, and quantitative MLPA analysis. Mutations were found in all 117 cases. Lof mutations in the VWF gene in the compound-heterozygous state were detected in two patients, two patients had pathogenic variants in the F9 gene, and one patient had a pathogenic variant in the F7 gene. These patients were excluded from further calculations. Intron 22 inversion was detected in 40% of cases, intron 1 inversion in 1% of cases, and gross deletions/duplications in 6% of cases. Point mutations accounted for 53%: missense mutations, 27%; small deletions, 10%; splice site mutations, 6%; nonsense mutations, 5%; and small duplications, 5%. Eighteen mutations were not described previously. Most of them are Lof mutations. Thus, it is necessary to employ different methods for the effective molecular diagnostics of hemophilia A.