Introduction: Hypertrophic cardiomyopathy (HCM) is a myocardial disease characterised by left ventricular hypertrophy unexplained by other abnormal loading conditions. At the genetic level, variants in sarcomeric genes are the most frequent cause of disease, with other non-sarcomeric causes such as RASopathies being reported in smaller proportions. The present study aims to evaluate the contribution of genes associated with RASopathies as a cause of disease in our cohort of HCM patients.

Methods: Retrospective study in which the presence of disease-associated variants in RAS-MAPK pathway genes (BRAF, HRAS, KRAS, LZTR1, PTPN11, RAF1, RIT1, SOS1, SOS2, CBL, MAP2K1, MAP2K2, NRAS, PPP1CB, RASA2, RRAS, SHOC2, SPRED1) was evaluated in patients referred to our centre for genetic study with a diagnosis of HCM.

Results: A total of 9,448 consecutive unrelated probands with suspected HCM have been sequenced by NGS (next-generation-sequencing) in our centre. In 2,663 (28%) we identified possibly pathogenic/pathogenic causal variants, including 28 individuals with RAS pathway genes (1.05%). The mean age at the time of the study was 38 years (range 1-81 years). Fourteen of these individuals had data suggestive (but not conclusive) of RASopathies. PTPN11 was the gene where pathogenic variants were most frequently identified, followed by RAF1, HRAS and KRAS. Two cases corresponded to mosaicism (in BRAF and SHOC2). In two of the families where the study in progenitors was possible the variant had a "de novo" presentation.

Conclusions: In our cohort of probands with HCM, 1% of cases variants associated with RASopathies were identified, with PTPN11 being the most frequent gene. Data suggestive (but not conclusive) of these diseases were described in only half of the cases. The inclusion of genes associated with RASopathies in targeted panels should be considered in order to increase the diagnostic yield in individuals with HCM, allowing an early aetiological diagnosis to plan an adequate follow-up and treatment.