Targeted next generation sequencing in a young population with suspected inherited malignant cardiac arrhythmias

Anders Krogh Broendberg,Lisbeth Noerum Pedersen,Henrik Kjaerulf Jensen,Morten Krogh Christiansen,Jens Cosedis Nielsen

doi:10.1038/s41431-017-0060-8

Abstract

Aborted sudden cardiac death in the young often is due to inherited heart disease. However, the clinical phenotype in these patients is not always evident. The aim of this study was to identify pathogenic molecular genetic variants in a population with suspected inherited cardiac arrhythmias. Eligible patients were admitted to Aarhus University Hospital, Denmark during the period 1999–2013 with arrhythmias assumed caused by a hereditary heart disease, and in whom no genotype had been established. We used the Danish national pacemaker and ICD registry to identify this cohort. One third (24/80) of the study population had first-line genetic testing with a targeted next-generation sequencing (NGS) panel, and two-third (56/80) of the study population had second-line genetic testing with NGS where prior Sanger sequencing did not reveal a causative variant. Variants were assessed according to the American College of Medical Genetics and Genomics (ACMG) guidelines. We included 80 patients. Median age (IQR) was 38 (28–43) years, 54 (68%) were males. First-line genetic testing identified a genetic variant in 33% (8/24) of the cases and second-line genetic testing revealed a variant in 20% (11/56) of the cases. Eleven variants were considered pathogenic, three likely pathogenic and 10 were variants of unknown significance (VUS). Seventeen variants were very rare with a minor allele frequency (MAF) ≤0.02% in all population databases used in the study. Molecular genetic testing of patients with suspected inherited cardiac arrhythmias with NGS identifies a molecular-genetic cause in a significant proportion of patients.

Highlights

Sudden cardiac death (SCD) from cardiac arrest accounts for an estimated 15–20% of all deaths [1]
We identified all patients ≤50 years of age treated with an Implantable Cardioverter Defibrillator (ICD) at Aarhus University Hospital from 1999 to 2013 (n = 433) using the Danish Pacemaker and ICD registry
In the present study 56 (70%) patients underwent secondline screening with a targeted next-generation sequencing (NGS) panel, where prior genetic screening using Sanger sequencing did not reveal a

Summary

Introduction

Sudden cardiac death (SCD) from cardiac arrest accounts for an estimated 15–20% of all deaths [1]. Coronary heart disease and valvular heart disease are the largest contributors to SCD in patients above the age of 35 years, whereas rare inherited cardiac disorders is the primary cause of SCD below the age of 35 years [1]. Rare inherited cardiac disorders are divided into two broad classes; cardiomyopathies and channelopathies. These diseases are mainly considered Mendelian disorders, where a strong monogenic component precipitates the risk of fatal or near fatal arrhythmic events [2]. Genetic channelopathies are caused by mutations in the genes encoding the pore forming subunit of the ion channels (alpha subunit) or the genes encoding the regulatory proteins [3]. Cardiomyopathies are caused by mutations in genes encoding the nucleus, the sarcomeric proteins and the desmosomal proteins causing abnormal myocardium [4]

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