Clinical and molecular genetic characteristics of 19 Russian patients with Noonan syndrome caused by variants in the RAF1

Introduction. RASopathy pathologies are a unique group of diseases with a multisystem lesion. In the structure of RASopathy, causal genetic variants of the RAF1 are the most common cause of HCM. Among all registered variants of the RAF1, the variant c.770C>T, p.S257L accounts for approximately 50% of cases. Due to the heterogeneity of clinical manifestations in patients with pathogenic variants of the RAF1 gene, the establishment of clinical and genetic features remains an urgent task. The aim of the study. To establish clinical and molecular genetic characteristics of Russian children with Noonan syndrome caused by variants of the RAF1 gene. Materials and methods. Single-center retrospective and prospective cohort study of a sample of ninety eight RASopathy patients aged from 1 month to 18 years. Results. In 19 of 98 patients with RASopathy, there were detected causal variants in the RAF1 gene, which amounted to 19.0%. All genetic variants detected in the RAF1 gene are localized in the cluster part of the gene in the CR2 domain. The c.770C>T, p.S257L variant was the cause of the disease in 10.22% of cases of all RASopathy diagnosed by us and 52.6% of cases of all children with RAF1 gene variants. All patients with RAF1 gene variants showed characteristic extracardiac signs of Noonan syndrome from the first months of life. Myocardial hypertrophy (MCH) was present in all patients, in the vast majority (89.4%) — with LVOT obstruction. When analyzing the course of remodeling, cases of MCH progression were more often noted (78.9%). In 35.7% of patients, one of the adverse cardiovascular events was recorded. Patients with the c.770C >T, p.S257L variant, compared with patients with other genetic variants, already from the first hospitalization demonstrated a more severe phenotype with pronounced signs of HF (p = 0.104), the highest level of NTproBNP (p = 0.003) and LVOTO (p = 0.040). Conclusion. RAF1 gene variants children demonstrate the classic phenotype of Noonan syndrome with the most severe damage to the cardiovascular system and require a comprehensive and dynamic examination with the involvement of specialists of various profiles.