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@article{Thomson:2019:10.1038/s41436-018-0375-z,
author = {Thomson, KL and Ormondroyd, E and Harper, AR and Dent, T and McGuire, K and Baksi, J and Blair, E and Brennan, P and Buchan, R and Bueser, T and Campbell, C and Carr-White, G and Cook, S and Daniels, M and Deevi, SVV and Goodship, J and Hayesmoore, JBG and Henderson, A and Lamb, T and Prasad, S and Rayner-Matthews, P and Robert, L and Sneddon, L and Stark, H and Walsh, R and Ware, JS and Farrall, M and Watkins, HC and NIHR, BioResource Rare Diseases Consortium},
doi = {10.1038/s41436-018-0375-z},
journal = {Genetics in Medicine},
pages = {1576--1584},
title = {Analysis of 51 proposed hypertrophic cardiomyopathy genes from genome sequencing data in sarcomere negative cases has negligible diagnostic yield},
url = {http://dx.doi.org/10.1038/s41436-018-0375-z},
volume = {21},
year = {2019}
}

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TY  - JOUR
AB  - 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.
AU  - Thomson,KL
AU  - Ormondroyd,E
AU  - Harper,AR
AU  - Dent,T
AU  - McGuire,K
AU  - Baksi,J
AU  - Blair,E
AU  - Brennan,P
AU  - Buchan,R
AU  - Bueser,T
AU  - Campbell,C
AU  - Carr-White,G
AU  - Cook,S
AU  - Daniels,M
AU  - Deevi,SVV
AU  - Goodship,J
AU  - Hayesmoore,JBG
AU  - Henderson,A
AU  - Lamb,T
AU  - Prasad,S
AU  - Rayner-Matthews,P
AU  - Robert,L
AU  - Sneddon,L
AU  - Stark,H
AU  - Walsh,R
AU  - Ware,JS
AU  - Farrall,M
AU  - Watkins,HC
AU  - NIHR,BioResource Rare Diseases Consortium
DO  - 10.1038/s41436-018-0375-z
EP  - 1584
PY  - 2019///
SN  - 1098-3600
SP  - 1576
TI  - Analysis of 51 proposed hypertrophic cardiomyopathy genes from genome sequencing data in sarcomere negative cases has negligible diagnostic yield
T2  - Genetics in Medicine
UR  - http://dx.doi.org/10.1038/s41436-018-0375-z
UR  - https://www.ncbi.nlm.nih.gov/pubmed/30531895
UR  - http://hdl.handle.net/10044/1/66820
VL  - 21
ER  -

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