Molecular characterization of individuals with RASopathies: Spectrum of genetic variants in a large Indian cohort

RASopathies are a group of developmental disorders caused by variations in genes of the RAS/mitogen activated protein kinase (MAPK) pathway and affect 1 in 1000 individuals worldwide. Due to overlapping clinical features, accurate diagnosis is challenging and therefore we used next-generation sequencing (NGS) panels as an effective molecular diagnostic tool. Targeted sequencing was performed on 130 samples using a multigene panel comprising of 21 RASopathy genes. Molecular analysis revealed variations in 74 individuals (57%). Pathogenic or likely pathogenic variations were observed in 60/74 (81%) of the cases, 13 (17.5%) had variant(s) of uncertain significance (VUS), and one novel variant was identified in RASA2 whose pathogenicity has not yet been established. In individuals with Noonan Syndrome, pathogenic variants were identified in eight different genes mainly PTPN11, SOS1, RAF1 and LZTR1. Nine clinically diagnosed Cardio-facio-cutaneous syndrome cases harboured variations in BRAF, MAP2K2 and MAP2K1 The c.34G>A variant in HRAS was seen in all nine individuals diagnosed with Costello syndrome. This study provides a comprehensive molecular and clinical profile of the largest Indian RASopathy cohort. The use of targeted gene panel has increased the variation detection rate in affected individuals.