Akademik Veri Yönetim Sistemi
Clinical Genetics, 2026 (SCI-Expanded, Scopus)
RASopathies are a group of genetically heterogeneous developmental disorders caused by germline variants affecting the RAS/MAPK signaling pathway. These disorders display overlapping clinical features and diverse molecular mechanisms. This study aimed to evaluate the clinical and molecular spectrum of patients diagnosed with RASopathies, with a particular focus on novel and rare variants. A retrospective, multicenter study was conducted on patients with clinically suspected RASopathy and diagnosed by targeted Next Generation Sequencing analysis between 2021 and 2024. Variants were classified according to ACMG criteria, and clinical data were reviewed for genotype–phenotype correlations. Among 23 patients (14 males, 9 females), 15 (65.2%) had Noonan syndrome, five (21.7%) Neurofibromatosis Type 1, two (8.7%) Cardio-facio-cutaneous syndrome, and one (4.3%) Neurofibromatosis–Noonan syndrome. The most frequent clinical findings were craniofacial dysmorphism (91.3%), musculoskeletal anomalies (82.6%), and cutaneous features (78.3%). A total of 24 heterozygous variants were identified in seven genes: PTPN11 (45.8%), NF1 (25%), LZTR1 (12.5%), and RASA2, SOS1, MAP2K1, and BRAF (each 4.2%). Four novel variants were detected (PTPN11 c.853 + 4A>G, RASA2 p.E71D, NF1 p.W784Mfs*10, MAP2K1 p.A106T). This study highlights the clinical and molecular heterogeneity of RASopathies and expands the variant spectrum with novel and rare pathogenic alterations. The identification of new variants, particularly in rarely implicated genes such as RASA2, underlines the diagnostic value of comprehensive NGS-based testing and the need for individualized, multidisciplinary clinical management.