Genetic Spectrum of Non-PTPN11 Variants in Noonan Syndrome and Related RASopathies: Findings From a Russian Cohort

Abstract

Noonan syndrome (NS) and related RASopathies form a clinically and genetically heterogeneous group of disorders caused by germline dysregulation of the RAS/MAPK pathway. Pathogenic variants in PTPN11 account for roughly half of classical NS, but the contribution of non-PTPN11 genes in patients referred with NS or Noonan-like phenotypes remains incompletely defined in several populations, including Russia. We characterized the spectrum of non-PTPN11 variants in a large Russian cohort referred for suspected NS or Noonan-like phenotypes and examined gene-specific clinical patterns. We analyzed 456 unrelated patients with clinically diagnosed NS or Noonan-related syndromes using a targeted panel of 23 RAS/MAPK pathway genes. PTPN11 variants (23% of cases) were reported previously; here we focused on the remaining patients. Pathogenic or likely pathogenic variants were identified in 19% of cases (85/456), with NF1, SOS1, SHOC2, and BRAF being the most frequently mutated genes, together accounting for 50% of the non-PTPN11 diagnoses. Novel variants were observed in 12.1% of cases (7/58 unique variants). Several genotype–phenotype associations emerged: SOS1 mutations were associated with a high prevalence of cardiac defects, especially pulmonary stenosis and atrial septal defects (64% of patients, p = 0.01), whereas NF1 and SPRED1 cases had significantly fewer cardiac anomalies (p < 0.001 and p < 0.05, respectively). Lentigines were predominantly seen in NF1 and SPRED1 patients (p < 0.01), and all three evaluable males with MAP2K1 variants had cryptorchidism (3/3). Conversely, BRAF-mutated patients showed lower incidence of chest deformity (p < 0.01) but higher rates of developmental delay. NF1, SOS1, SHOC2, and BRAF together accounted for half of the non-PTPN11 molecular diagnoses in this Russian cohort, and the observed gene-specific clinical patterns align with previous series, although limited subgroup sizes preclude firm individual associations.