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Analysis of 51 proposed hypertrophic cardiomyopathy genes from genome sequencing data in sarcomere negative cases has negligible diagnostic yield
- Source :
- Genetics in medicine : official journal of the American College of Medical Genetics
- Publication Year :
- 2018
- Publisher :
- Springer Nature [academic journals on nature.com], 2018.
-
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.
- Subjects :
- Adult
Male
Sarcomeres
Adolescent
NIHR BioResource – Rare Diseases Consortium
VARIANTS
GUIDELINES
Article
DISEASE
genetic testing
Young Adult
RARE
evidence-based
Humans
Genetic Association Studies
Aged
Genetics & Heredity
0604 Genetics
Science & Technology
Whole Genome Sequencing
MUTATIONS
variant interpretation
1103 Clinical Sciences
Cardiomyopathy, Hypertrophic
Middle Aged
HCM
VUS
Case-Control Studies
Female
Life Sciences & Biomedicine
TASK-FORCE
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Journal :
- Genetics in medicine : official journal of the American College of Medical Genetics
- Accession number :
- edsair.pmid.dedup....4fb0f4ad0a47c21d444ebceb67ff31a7