The Impact of Paternal Age on RASopathies: Insights from a Clinical Case Series

Aim: RASopathies are a group of genetic disorders caused by germline mutations in genes involved in the RAS/MAPK signaling pathway. These syndromes, including Noonan, Costello, and cardiofaciocutaneous (CFC syndromes, are typically inherited in an autosomal dominant manner but often occur sporadically due to de novo mutations. To reassess our single-center case series with clearer framing of the paternal age effect (PAE), strengthen interpretability with explicit terminology, expanded limitations, and pragmatic clinical implications. Methods: We retrospectively reviewed 25 clinically and molecularly confirmed RASopathy cases diagnosed at Ümraniye Training and Research Hospital (2018-2022). Six patients with inherited variants were excluded, leaving 19 cases with de novo variants for analysis. For each proband, we documented the causal gene/variant, inheritance, and paternal age at conception. Analyses are descriptive; no control cohort was available. Results: Mutations were most frequently identified in SOS1 (36.8%) and PTPN11 (26.3%). All 19 patients harbored de novo mutations, and two mutations (in RAF1 and NF1) were classified as novel. Paternal ages ranged from 25 to 43 years, with a mean of 34.0 years and a median of 33 years. Nine fathers (47.4%) were aged ≥35 years, consistent with the commonly accepted threshold for advanced paternal age. Conclusion: This series is consistent with a paternal age effect in RAS/MAPK–activating disorders. Given the modest sample and lack of controls, causal inference is limited. We outline practical counseling points and a prospective design to validate PAE magnitude in our setting.