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Genet Med. 2018 Dec 11. doi: 10.1038/s41436-018-0375-z. [Epub ahead of print]

Analysis of 51 proposed hypertrophic cardiomyopathy genes from genome sequencing data in sarcomere negative cases has negligible diagnostic yield.

Author information

1
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
2
Oxford Medical Genetics Laboratories, Oxford University Hospitals NHS Foundation Trust, The Churchill Hospital, Oxford, UK.
3
National Heart and Lung Institute, Imperial College London, London, UK.
4
Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
5
Northern Genetics Service, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, UK.
6
Cardiovascular Research Centre, Royal Brompton & Harefield Hospitals NHS Foundation Trust, London, UK.
7
King's College London, Guy's & St Thomas' Hospital NHS Foundation Trust, King's College Hospital NHS Foundation Trust, London, UK.
8
Guy's & St Thomas' Hospital NHS Foundation Trust, London, UK.
9
National Heart Research Institute Singapore, National Heart Centre Singapore, Singapore, Singapore.
10
Division of Cardiovascular & Metabolic Disorders, Duke-National University of, Singapore, Singapore.
11
MRC London Institute of Medical Sciences, Imperial College London, London, UK.
12
Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, UK.
13
NIHR BioResource, Cambridge University Hospitals NHS Foundation, Cambridge Biomedical Campus, Cambridge, UK.
14
The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
15
Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK. hugh.watkins@rdm.ox.ac.uk.
16
The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK. hugh.watkins@rdm.ox.ac.uk.

Abstract

PURPOSE:

Increasing numbers of genes are being implicated in Mendelian disorders and incorporated into clinical test panels. However, lack of evidence supporting the gene-disease relationship can hinder interpretation. We explored the utility of testing 51 additional genes for hypertrophic cardiomyopathy (HCM), one of the most commonly tested Mendelian disorders.

METHODS:

Using genome sequencing data from 240 sarcomere gene negative HCM cases and 6229 controls, we undertook case-control and individual variant analyses to assess 51 genes that have been proposed for HCM testing.

RESULTS:

We found no evidence to suggest that rare variants in these genes are prevalent causes of HCM. One variant, in a single case, was categorized as likely to be pathogenic. Over 99% of variants were classified as a variant of uncertain significance (VUS) and 54% of cases had one or more VUS.

CONCLUSION:

For almost all genes, the gene-disease relationship could not be validated and lack of evidence precluded variant interpretation. Thus, the incremental diagnostic yield of extending testing was negligible, and would, we propose, be outweighed by problems that arise with a high rate of uninterpretable findings. These findings highlight the need for rigorous, evidence-based selection of genes for clinical test panels.

KEYWORDS:

HCM; VUS; evidence-based; genetic testing; variant interpretation

PMID:
30531895
DOI:
10.1038/s41436-018-0375-z

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