{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T13:13:22Z","timestamp":1792761202602,"version":"4.5.0"},"reference-count":92,"publisher":"BMJ","issue":"4","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2013,1,9]]},"published-print":{"date-parts":[[2013,4]]},"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and results<\/jats:title>\n                    <jats:p>\n                      223 unrelated patients with HCM (46\u00b115\u2005years 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\u2005Mb target region was 120. Rare (frequency&lt;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 (\n                      <jats:italic>MYH7<\/jats:italic>\n                      ,\n                      <jats:italic>MYBPC3<\/jats:italic>\n                      ,\n                      <jats:italic>TNNI3<\/jats:italic>\n                      ,\n                      <jats:italic>TNNT2<\/jats:italic>\n                      ) 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%).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>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.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/jmedgenet-2012-101270","type":"journal-article","created":{"date-parts":[[2013,2,8]],"date-time":"2013-02-08T23:40:29Z","timestamp":1360366829000},"page":"228-239","source":"Crossref","is-referenced-by-count":211,"title":["Genetic complexity in hypertrophic cardiomyopathy revealed by high-throughput sequencing"],"prefix":"10.1136","volume":"50","author":[{"given":"Luis R","family":"Lopes","sequence":"first","affiliation":[{"name":"UCL Institute of Cardiovascular Science, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Zekavati","sequence":"additional","affiliation":[{"name":"Department of Molecular Haematology and Cancer Biology, UCL Genomics, UCL Institute of Child Health, London, 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