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Publication Detail
Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Journal Article
  • Authors:
    Lopes LR, Zekavati A, Syrris P, Hubank M, Giambartolomei C, Dalageorgou C, Jenkins S, McKenna W, Uk10k Consortium , Plagnol V, Elliott PM
  • Publication date:
    04/2013
  • Pagination:
    228, 239
  • Journal:
    J Med Genet
  • Volume:
    50
  • Issue:
    4
  • Status:
    Published
  • Country:
    England
  • PII:
    jmedgenet-2012-101270
  • Language:
    eng
  • Keywords:
    Adult, Amino Acid Substitution, Cardiomyopathy, Hypertrophic, Female, High-Throughput Nucleotide Sequencing, Humans, Male, Middle Aged, Mutation, Pedigree, Polymorphism, Single Nucleotide, Sarcomeres
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.
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