Analysis of the features of neurofibromatosis type 1 in the Republic of Bashkortostan

Neurofibromatosis type 1 (NF1) is an autosomal dominant hereditary tumor syndrome that occurs on average with a frequency of 1: 3000 people. Clinical features of NF1 include cafe-au-lait macules on the skin, multiple cutaneous, subcutaneous, and plexi-form neurofibromas, Lisch nodules, and optic gliomas. The disease is also characterized by damage to the musculoskeletal system, impaired intelligence and behavior. The cause of the disease is germinal mutations in the NF1 gene, which encodes the oncosuppressor neurofibromin. NF1 is characterized by pronounced polymorphism of clinical manifestations, from erased to severe, without geno-phenotypic correlations. Therefore, the role of modifier genes in the pathogenesis of NF1 is assumed. We carried out a clinical-epidemiological and molecular-genetic study of patients with NF1 from the Republic of Bashkortostan (RB). We searched for intragenic mutations by sequencing 57 exons of the NF1 gene, and identified deletions of the entire gene using microsatellite analysis. The prevalence of NF1 in RB is 10 per 100 000. We identified 14 intragenic mutations in the NF1 gene in 20 patients with NF1 and 2 extended deletion of NF1 gene in 3 patients from 2 unrelated families. We did not find a correlation between the type of mutation and the characteristics of the clinical manifestations of the disease. To determine the possible influence of modifier genes on pathogenesis of NF1, we carried out a comparative analysis of the clinical manifestations of NF1 depending on inheritance, ethnicity and association of systemic manifestations. Among the clinical manifestations of NF1 in RB, there was a low frequency of optic nerve gliomas (5,25%) and plexiform neurofibromas (5%). The incidence of brain cysts was 4,25% among patients with NF1. We identified 9 mutations for the first time in the world, 5 out of 14 identified mutations are known (c.2806A>T, c.2991-1G>C, c.3158C>G, c.4537C>T, c.6792C>A). The distribution of mutation types turned out to be random. We identified a protective role of crossbreeding for the development of severe manifestations of NF1. We determined a high incidence of scoliosis, short stature, facial dysmorphism and chest deformity in the inheritance of NF1 from the mother, which suggests the influence of modifier genes on the pathogenesis of NF1.