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Atlas of the clinical genetics of human dilated cardiomyopathy

Haas, J; Frese, KS; Peil, B; Kloos, W; Keller, A; Nietsch, R; Feng, Z; ... Meder, B; + view all (2015) Atlas of the clinical genetics of human dilated cardiomyopathy. European Heart Journal , 36 (18) 1123-U43. 10.1093/eurheartj/ehu301. Green open access

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Abstract

AIM: Numerous genes are known to cause dilated cardiomyopathy (DCM). However, until now technological limitations have hindered elucidation of the contribution of all clinically relevant disease genes to DCM phenotypes in larger cohorts. We now utilized next-generation sequencing to overcome these limitations and screened all DCM disease genes in a large cohort. METHODS AND RESULTS: In this multi-centre, multi-national study, we have enrolled 639 patients with sporadic or familial DCM. To all samples, we applied a standardized protocol for ultra-high coverage next-generation sequencing of 84 genes, leading to 99.1% coverage of the target region with at least 50-fold and a mean read depth of 2415. In this well characterized cohort, we find the highest number of known cardiomyopathy mutations in plakophilin-2, myosin-binding protein C-3, and desmoplakin. When we include yet unknown but predicted disease variants, we find titin, plakophilin-2, myosin-binding protein-C 3, desmoplakin, ryanodine receptor 2, desmocollin-2, desmoglein-2, and SCN5A variants among the most commonly mutated genes. The overlap between DCM, hypertrophic cardiomyopathy (HCM), and channelopathy causing mutations is considerably high. Of note, we find that >38% of patients have compound or combined mutations and 12.8% have three or even more mutations. When comparing patients recruited in the eight participating European countries we find remarkably little differences in mutation frequencies and affected genes. CONCLUSIONS: This is to our knowledge, the first study that comprehensively investigated the genetics of DCM in a large-scale cohort and across a broad gene panel of the known DCM genes. Our results underline the high analytical quality and feasibility of Next-Generation Sequencing in clinical genetic diagnostics and provide a sound database of the genetic causes of DCM.

Type: Article
Title: Atlas of the clinical genetics of human dilated cardiomyopathy
Open access status: An open access version is available from UCL Discovery
DOI: 10.1093/eurheartj/ehu301
Publisher version: http://dx.doi.org/10.1093/eurheartj/ehu301
Language: English
Additional information: This is a pre-copyedited, author-produced PDF of an article accepted for publication in European Heart Journal following peer review. The version of record Atlas of the clinical genetics of human dilated cardiomyopathy, Jan Haas et. al., in: European Heart Journal May 2015, 36 (18) 1123-1135; DOI: 10.1093/eurheartj/ehu301 is available online at: http://dx.doi.org/10.1093/eurheartj/ehu301
Keywords: Science & Technology, Life Sciences & Biomedicine, Cardiac & Cardiovascular Systems, Cardiovascular System & Cardiology, Cardiomyopathy, Genetics, Patients, Diagnosis, Right-Ventricular Dysplasia/cardiomyopathy, Cardiology Working Group, Genome-Wide Association, Heart-Failure, Pericardial Diseases, Position Statement, European-Society, Dna Methylation, Mutation, Classification
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Div of Biosciences > Genetics, Evolution and Environment
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Pop Health Sciences > Institute of Cardiovascular Science > Clinical Science
URI: https://discovery.ucl.ac.uk/id/eprint/1447311
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