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Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing.

Lopes, LR; Zekavati, A; Syrris, P; Hubank, M; Giambartolomei, C; Dalageorgou, C; Jenkins, S; (2013) Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing. J Med Genet , 50 (4) pp. 228-239. 10.1136/jmedgenet-2012-101270. Gold open access

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 (frequency<0.5%) non-synonymous, loss-of-function and splice-site variants were defined as candidates. Excluding titin, we identified 152 distinct candidate variants in sarcomeric or associated genes (89 novel) in 143 patients (64%). Four sarcomeric genes (MYH7, 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.

Type: Article
Title: Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing.
Location: England
Open access status: An open access publication
DOI: 10.1136/jmedgenet-2012-101270
Keywords: Adult, Amino Acid Substitution, Cardiomyopathy, Hypertrophic, Female, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Mutation, Pedigree, Polymorphism, Single Nucleotide, Sarcomeres
UCL classification: UCL > School of Life and Medical Sciences
UCL > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of)
UCL > School of Life and Medical Sciences > Faculty of Life Sciences > Biosciences (Division of) > Genetics, Evolution and Environment > UCL Genetics Institute
UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
UCL > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Child Health
URI: http://discovery.ucl.ac.uk/id/eprint/1386493
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