Variant panorama in 1,385 index patients and sensitivity of expanded next-generation sequencing panels in...

Arrhythmogenic disorders occur in a broad spectrum of cardiac pathologies in the general population with a prevalence of 1:10,000 to 1:500. Genetic studies conducted during the past 20 years have markedly illuminated the genetic basis of inherited cardiac disorders. However, uncertainty exists regarding which genes should be included and routinely assessed on genetic testing panels. Here, we review the genetic basis of the most important arrhythmogenic disorders found in our laboratory since 2016 by next-generation sequencing (NGS) analysis.

We analyzed sequence data from 1,385 clinical index cases with a suspected diagnosis of long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), hypertrophic cardiomyopathy (HCM), dilatative cardiomyopathy (DCM) or arrhythmogenic right ventricular cardiomyopathy (ARVC). Genetic testing was performed by NGS using a custom design based on an Agilent SureSelect^QXT.

The detection rate of pathogenic or likely pathogenic variants was in the range of 16% for BrS to 40% for HCM. Only the few well known core genes and some additional side genes substantially contribute to the diagnostic sensitivity.

Clinical testing provides a definitive diagnosis for many patients. The genetic result may be important for risk stratification, genetic counseling and, in some cases, treatment planning. Diagnostic panels should not be further expanded as inclusion of many genes rather produces variants of unclear significance and confusing reports.