Genotype‐cardiac phenotype correlations in a large single‐center cohort of patients affected by RASopathies: Clinical implications and literature review

Abstract

Congenital heart disease (CHD) and hypertrophic cardiomyopathy (HCM) are common features in patients affected by RASopathies. The aim of this study was to assess genotype‐ phenotype correlations, focusing on the cardiac features and outcomes of interventions for cardiac conditions, in a single‐center cohort of 116 patients with molecularly confirmed diagnosis of RASopathy, and compare these findings with previously published data. All enrolled patients underwent a comprehensive echocardiographic examination. Relevant information was also retrospectively collected through the analysis of clinical records. As expected, significant associations were found between PTPN11 mutations and pulmonary stenosis (both valvular and supravalvular) and pulmonary valve dysplasia, and between SOS1 mutations and valvular defects. Similarly, HRAS mutations were significantly associated with HCM. Potential associations between less prevalent mutations and cardiac defects were also observed, including RIT1 mutations and HCM, SOS2 mutations and septal defects, and SHOC2 mutations and septal and valve abnormalities. Patients with PTPN11 mutations were the most likely to require both a primary treatment (transcatheter or surgical) and surgical reintervention. Other cardiac anomalies less reported until recently in this population, such as isolated functional and structural mitral valve diseases, as well as a sigmoid‐shaped interventricular septum in the absence of HCM, were also reported. In conclusion, our study confirms previous data but also provides new insights on cardiac involvement in RASopathies. Further research concerning genotype/phenotype associations in RASopathies could lead to a more rational approach to surgery and the consideration of drug therapy in patients at higher risk due to age, severity, anatomy, and comorbidities.

Neurologic and neurodevelopmental complications in cardiofaciocutaneous syndrome are associated with genotype: A multinational cohort study

“…Owing to small sample sizes, previous investigations have frequently lumped together individuals with MAP2K1/2 variants into a single cohort to compare relative to those with BRAF variants. 13,16,18,36 Our findings suggest that this practice may disguise significant distinctions in the clinical presentation of these subgroups. Specifically, with regard to neurologic features, MAP2K2 variants were associated with lower risk of severe neurodevelopmental disability and epilepsy than MAP2K1 variants.…”

Clinical overview on RASopathies

“…Cardiovascular system involvement is present in up to 80% of patients, with pulmonary valve stenosis and hypertrophic cardiomyopathy (HCM) being the most characteristic heart abnormalities throughout the different entities (Calcagni et al, 2017; Leoni, Blandino, et al, 2022). Septal defects represent the third most common type of anomaly, but are of lower specificity for RASopathies.…”

Smith Magenis syndrome: First case of congenital heart defect in a patient with Rai1 mutation

“…Pulmonary valve stenosis is a congenital cardiac defect frequently associated with a variety of genetic conditions (Leoni et al, 2021). When detected during the prenatal life a genetic disorder should be suspected, especially in the presence of other fetal anomalies, leading to an early diagnosis (Lei et al, 2016).…”