Genotype-cardiac phenotype correlations in a large single-center cohort of patients affected by Rasopathies: clinical implications and literature review

Congenital heart disease (CHD) and hypertrophic cardiomyopathy (HCM) are com-mon features in patients affected by RASopathies. The aim of this study was toassess genotype- phenotype correlations, focusing on the cardiac features and out-comes of interventions for cardiac conditions, in a single-center cohort of116 patients with molecularly confirmed diagnosis of RASopathy, and compare thesefindings with previously published data. All enrolled patients underwent a compre-hensive echocardiographic examination. Relevant information was also retrospec-tively collected through the analysis of clinical records. As expected, significantassociations were found betweenPTPN11mutations and pulmonary stenosis (bothvalvular and supravalvular) and pulmonary valve dysplasia, and betweenSOS1muta-tions and valvular defects. Similarly,HRASmutations were significantly associatedwith HCM. Potential associations between less prevalent mutations and cardiacdefects were also observed, includingRIT1mutations and HCM,SOS2mutations andseptal defects, andSHOC2mutations and septal and valve abnormalities. PatientswithPTPN11mutations were the most likely to require both a primary treatment(transcatheter or surgical) and surgical reintervention. Other cardiac anomalies lessreported until recently in this population, such as isolated functional and structuralmitral valve diseases, as well as a sigmoid-shaped interventricular septum in theabsence of HCM, were also reported. In conclusion, our study confirms previous databut also provides new insights on cardiac involvement in RASopathies. Furtherresearch concerning genotype/phenotype associations in RASopathies could lead toa more rational approach to surgery and the consideration of drug therapy in patientsat higher risk due to age, severity, anatomy, and comorbidities