Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing
Open Access
- 8 February 2013
- journal article
- genotype phenotype-correlations
- Published by BMJ in Journal of Medical Genetics
- Vol. 50 (4), 228-239
- https://doi.org/10.1136/jmedgenet-2012-101270
Abstract
Background Clinical interpretation of the large number of rare variants identified by high throughput sequencing (HTS) technologies is challenging. The aim of this study was to explore the clinical implications of a HTS strategy for patients with hypertrophic cardiomyopathy (HCM) using a targeted HTS methodology and workflow developed for patients with a range of inherited cardiovascular diseases. By comparing the sequencing results with published findings and with sequence data from a large-scale exome sequencing screen of UK individuals, we sought to quantify the strength of the evidence supporting causality for detected candidate variants. Methods and results 223 unrelated patients with HCM (46±15 years at diagnosis, 74% males) were studied. In order to analyse coding, intronic and regulatory regions of 41 cardiovascular genes, we used solution-based sequence capture followed by massive parallel resequencing on Illumina GAIIx. Average read-depth in the 2.1 Mb target region was 120. Rare (frequencyMYH7, MYBPC3, TNNI3, TNNT2) showed an excess of rare single non-synonymous single-nucleotide polymorphisms (nsSNPs) in cases compared to controls. The estimated probability that a nsSNP in these genes is pathogenic varied between 57% and near certainty depending on the location. We detected an additional 94 candidate variants (73 novel) in desmosomal, and ion-channel genes in 96 patients (43%). Conclusions This study provides the first large-scale quantitative analysis of the prevalence of sarcomere protein gene variants in patients with HCM using HTS technology. Inclusion of other genes implicated in inherited cardiac disease identifies a large number of non-synonymous rare variants of unknown clinical significance.Keywords
This publication has 94 references indexed in Scilit:
- Genetic variation in the alternative splicing regulator RBM20 is associated with dilated cardiomyopathyHeart Rhythm, 2012
- Truncations of Titin Causing Dilated CardiomyopathyThe New England Journal of Medicine, 2012
- Electrocardiographic Features of Sarcomere Mutation Carriers With and Without Clinically Overt Hypertrophic CardiomyopathyThe American Journal of Cardiology, 2011
- A rare variant in MYH6 is associated with high risk of sick sinus syndromeNature Genetics, 2011
- A map of human genome variation from population-scale sequencingNature, 2010
- ANNOVAR: functional annotation of genetic variants from high-throughput sequencing dataNucleic Acids Research, 2010
- The RYR2-Encoded Ryanodine Receptor/Calcium Release Channel in Patients Diagnosed Previously With Either Catecholaminergic Polymorphic Ventricular Tachycardia or Genotype Negative, Exercise-Induced Long QT Syndrome: A Comprehensive Open Reading Frame Mutational AnalysisJournal of the American College of Cardiology, 2009
- The Sequence Alignment/Map format and SAMtoolsBioinformatics, 2009
- Shared Genetic Causes of Cardiac Hypertrophy in Children and AdultsThe New England Journal of Medicine, 2008
- Novel mechanism for sudden infant death syndrome: Persistent late sodium current secondary to mutations in caveolin-3Heart Rhythm, 2007