Next-generation sequencing identifies multiple disease associated variants in inherited heart conditions

Background: Inherited cardiomyopathies and arrhythmias are mainly autosomal dominant conditions characterized by incomplete penetrance and variable clinical expression. The introduction of Next-Generation Sequencing (NGS) panels and exome analysis for research and also diagnostic purposes do allow a comprehensive genetic analysis of all known genes as well as the discovery of novel genes for those conditions. However, the results often raise more questions than answers in particular in terms of proving causality of the identified variants. Methods and results: Here we report three families where we found more than one pathogenic variant in the index case. The analysis was done using NGS panels consisting of nearly 70 known genes for inherited cardiomyopathies and arrhythmias and/or whole exome sequencing. In a Long QT family the index case presented with syncope and a QTc interval of 520ms. An epinephrine drug challenge prolonged the QT interval up to 612ms and led to Torsade de Pointes with a transition to ventricular fibrillation in the recovery period. She was found to carry two previously reported disease causing mutations, one in KCNQ1 (p.R518X) and one in SCN5A (p.F1617del). Both parents who are clinically unaffected carry one mutation. In another family with left ventricular non-compaction cardiomyopathy the index patient was found to carry two novel MYH7 variants (p.R1677C; p.Q44X), both presumed to be pathogenic. Further analysis will show if those mutations are in "cis" or "trans" inherited and how they segregate in other affected family members. The third, most interesting family consists of four living and two deceased members who all presented with a heart block requiring pacemakers in their 30is.The index case has had additional features such as cardiomyopathy and a prolonged QT interval. She also survived a ventricular fibrillation arrest. Exome analysis found a frameshift mutation in RBM20 (p.S268DfsX3) in the index case, very likely causing her arrhythmic cardiomyopathy. Interestingly, this mutation did not segregate in any of the other family members affected by the heart block suggesting two different very rare inherited cardiac conditions in one family. Conclusion: NGS allows a comprehensive way of mutation detection which more and more uncovers the complexity of previously thought monogenetic conditions. Our data point out the importance of a thoughtful approach of genetic data interpretation especially in clinical settings and the careful usage for predictive testing in family members with potential life threatening arrhythmias.

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