Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing. Issue 4 (8th February 2013)

• Record Type: Journal Article
• Authors: Lopes, Luis R; Zekavati, Anna; Syrris, Petros; Hubank, Mike; Giambartolomei, Claudia; Dalageorgou, Chrysoula; Jenkins, Sharon; McKenna, William; Plagnol, Vincent; Elliott, Perry M
• Is Part Of: Journal of medical genetics. Volume 50:Issue 4(2013)
• Page Start: 228
• Page End: 239
• Publication Date: 2013-02-08
• Subjects: Hypertrophic Cardiomyopathy -- Genetics -- High-throughput sequencing; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2012-101270
• Languages: English
• ISSNs: 1468-6244

Abstract

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.