Spectrum of Causative Mutations in Patients with Hemophilia A in Russia.

Hemophilia A (HA) is one of the most widespread, X-linked, inherited bleeding disorders, which results from defects in the F8 gene. Nowadays, more than 3500 different pathogenic variants leading to HA have been described. Mutation analysis in HA is essential for accurate genetic counseling of patients and their relatives. We analyzed patients from 273 unrelated families with different forms of HA. The analysis consisted of testing for intron inversion (inv22 and inv1), and then sequencing all functionally important F8 gene fragments. We identified 101 different pathogenic variants in 267 patients, among which 35 variants had never been previously reported in international databases. We found inv22 in 136 cases and inv1 in 12 patients. Large deletions (1-8 exons) were found in 5 patients, and we identified a large insertion in 1 patient. The remaining 113 patients carried point variants involving either single nucleotide or several consecutive nucleotides. We report herein the largest genetic analysis of HA patients issued in Russia.

New missense mutation p.Trp387Ser affecting the functionally important TrpXXTrp motif in the TSR1 repeat of ADAMTS13 metalloproteinase: Case report.

Upshaw-Schulman syndrome (USS)-rare autosomal recessive disease that affects <1/1 000 000 individuals. It is characterized by the massive formation of platelet thrombi in the microcirculation accompanied by haemolytic anaemia, thrombocytopenia and clinical and laboratory signs of renal and neurological failure. USS is caused by mutations in the ADAMTS13 gene. Mutations in the ADAM metallopeptidase with thrombospondin type 1 motif 13  (ADAMTS13) gene can lead to disruption of secretion of this enzyme, or to decrease of enzyme proteinase activity without effect on ADAMTS13 secretion. The aim of this work is to describe a clinical case of USS caused by a new missense mutation in the ADAMTS13 gene. The diagnosis of thrombotic thrombocytopenic purpura was based on clinical signs and confirmed if plasma ADAMTS13 activity was <10%. ADAMTS13 gene sequencing was performed by the Sanger method using oligonucleotide primers of our own design. We found a new, undescribed mutation p.Trp387Ser in a TrpXXTrp motif. Previously, a pathogenic variation disrupting the 387TrpSerSerTrp390 motif of the ADAMTS13 protein was detected only once. Clinical picture of a patient with the combination of the p.Trp387Ser and p.Arg1060Trp variations is quite similar to that of the homozygous state of p.Arg1060Trp variant.