Genetic diagnosis of Cardiomyopathies

Circulation: Cardiovascular Genetics.
2011; 4: 110-122

Targeted Next-Generation Sequencing for the Molecular Genetic Diagnostics of Cardiomyopathies

Benjamin Meder, MD*, Jan Haas, MS*, Andreas Keller, PhD, Christiane Heid, MS, Steffen Just, PhD, Anne Borries, MS, Valesca Boisguerin, PhD, Maren Scharfenberger-Schmeer, PhD, Peer Stähler;, Markus Beier, PhD, Dieter Weichenhan, PhD, Tim M. Strom, MD, Arne Pfeufer, MD, PhD, Bernhard Korn, PhD, Hugo A. Katus, MD and Wolfgang Rottbauer, MD
+ Author Affiliations

From the Department of Internal Medicine III (B.M., J.H., C.H., S.J., H.A.K., W.R.), University of Heidelberg; Biomarker Discovery Center (A.K.); febit biomed gmbh (A.B., V.B., P.S., M.B.); and German Cancer Research Center (DKFZ) (M.S.-S., D.W., B.K.), Heidelberg, Germany; Institute of Human Genetics (T.M.S.), Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany; Institute of Human Genetics (A.P.), Klinikum rechts der Isar, Technische Universität München, Munich, Germany; and Department of Internal Medicine II (W.R.), University of Ulm, Ulm, Germany.

Abstract

Background— Today, mutations in more than 30 different genes have been found to cause inherited cardiomyopathies, some associated with very poor prognosis. However, because of the genetic heterogeneity and limitations in throughput and scalability of current diagnostic tools up until now, it is hardly possible to genetically characterize patients with cardiomyopathy in a fast, comprehensive, and cost-efficient manner.

Methods and Results— We established an array-based subgenomic enrichment followed by next-generation sequencing to detect mutations in patients with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM). With this approach, we show that the genomic region of interest can be enriched by a mean factor of 2169 compared with the coverage of the whole genome, resulting in high sequence coverage of selected disease genes and allowing us to define the genetic pathogenesis of cardiomyopathies in a single sequencing run. In 6 patients, we detected disease-causing mutations, 2 microdeletions, and 4 point mutations. Furthermore, we identified several novel nonsynonymous variants, which are predicted to be harmful, and hence, might be potential disease mutations or modifiers for DCM or HCM.

Conclusions— The approach presented here allows for the first time a comprehensive genetic screening in patients with hereditary DCM or HCM in a fast and cost-efficient manner.