Clinical and genetic polymorphism of RASopathies in patients with left ventricular hypertrophy

RASopathies are a heterogeneous group of diseases caused by genetic alteration of the RAS-MAPK pathway, which are characterized by multisystem symptoms, including short stature, facial dysmorphia, and a wide range of cardiac manifestations.

The aim of the study was to evaluate the spectrum of genetic causes and clinical manifestations of RASopathies in patients with left ventricular hypertrophy (LVH). We examined 180 probands with LVH which require surgical treatment, and found 19 rare variants in the genes encoding RASMAPK proteins in 18 probands (1-68 years). In 15 patients (4.5%), the diagnosis of RASopathy was confirmed by the detection of causative variants in the PTPN11, RIT1, LZTR1, MRAS, and HRAS genes. The primary diagnosis was Noonan syndrome in 6 patients, and hypertrophic cardiomyopathy in 9 patients. Two probands with RIT1 mutations had a macrosomal phenotype which was not typical for RASopathies. During the follow-up, 4 probands died, and 1 underwent a heart transplant. Three probands with LVH were found to have rare VUS, which contribution requires further study.

Conclusions: despite the well-known phenotype, many patients with RASopathies have not been clinically diagnosed. The phenotypic spectrum of RIT1 mutations can be expanded with macrosomy. In the presence of LVH, patients with rasopathies have an earlier manifestation and age of surgery, and a worse prognosis compared to non-syndromal HCM patients.

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