Cardiac hereditary diseases: genetic insights from a single center 15-year experience

Abstract

Abstract Funding Acknowledgements Type of funding sources: None. Background In the last decades, the implementation of high-throughput next-generation (NGS) technologies has profoundly changed the landscape of human genome sequencing. However, the molecular diagnosis in cardiac hereditary diseases is still hampered by the incomplete penetrance, variable expressivity, and genetic heterogeneity of the diseases. Objective We report our 15-year experience on a cohort of consecutive patients (pts) with suspicion of cardiac hereditary disease referred to the specialized cardiogenetic outpatient clinic of our center. Methods We retrospectively reviewed DNA sequencing results of pts referred to our center from July 1st 2007 through December 31st 2021, who were tested with NGS technologies for suspected cardiac hereditary diseases including channelopathies, inherited cardiomyopathies and unexplained sudden cardiac death. Results Among the 488 tested pts, the most frequent clinical indication were presymptomatic screening (37.3%) for a known familial variant, followed by suspected arrhythmic syndrome (28.3%) and hereditary cardiomyopathy (26.8%). A likely pathogenic/pathogenic variant was found in 198 pts for an overall diagnostic yield of 40.6% and of 23.6% considering only index cases. The rate of identified mutation-carriers was higher among pts with cardiomyopathy (45.8%) than among pts with inherited arrhythmic syndromes (37%). Panel A and B display variant distribution in arrhythmic syndromes and cardiomyopathies respectively. In particular, the highest diagnostic yield was observed among pts with suspected hypertrophic cardiomyopathy (60.7%) and catecholaminergic polymorphic ventricular tachycardia (50%), followed by congenital long QT syndrome (48.6%). The pathogenic variants were mainly identified in genes with definitive scientific evidence of causal association with the disease. Conclusions The 15-year experience of our specialized cardiogenetic outpatient clinic has demonstrated the pivotal role of genetic analysis for the diagnostic confirmation and, hence for the therapeutic management of pts with suspected cardiac hereditary disease.