ArticleGenetics in medicine : official journal of the American College of Medical Genetics2019
Analysis of 51 proposed hypertrophic cardiomyopathy genes from genome sequencing data in sarcomere negative cases has negligible diagnostic yield.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2019. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 36 papers, 1 of them a synthesis that pooled it.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
36 citing papers in PubMed, 1 synthesis or guideline pooled it, 63 citations in OpenAlex.
- A multiancestry polygenic risk score improves stratification in patients with hypertrophic cardiomyopathy.Nature cardiovascular research · 2026Pooled it
- Leveraging Large and Diverse Biobanks to Evaluate Gene-Disease Associations in Hypertrophic Cardiomyopathy.Journal of personalized medicine · 2026Article
- Genetics of Sudden Cardiac Death.Diseases (Basel, Switzerland) · 2025Review
- Clinically Actionable Hypertrophic Cardiomyopathy Genes in South Asian Indian Patients.Journal of the American Heart Association · 2025Article
- Pyruvate Dehydrogenase Kinase 4 Underlies the Metabolic Disorder of Cardiomyocytes in Patients With Hypertrophic Cardiomyopathy From Hypertrophy to Heart Failure.Journal of the American Heart Association · 2025Article
- GEO combined with quantitative protein trait loci identify causative proteins in hypertrophic cardiomyopathy.ESC heart failure · 2025Article
- An ALPK3 truncation variant causing autosomal dominant hypertrophic cardiomyopathy is partially rescued by mavacamten.Scientific reports · 2025Article
- Twin Phenomena of Hypertrophic Cardiomyopathy: A Reported Case Series.Anatolian journal of cardiology · 2024Review
- Dilated Cardiomyopathy: A Genetic Journey from Past to Future.International journal of molecular sciences · 2024Review
- Toward robust clinical genome interpretation: Developing a consistent terminology to characterize Mendelian disease-gene relationships-allelic requirement, inheritance modes, and disease mechanisms.Genetics in medicine : official journal of the American College of Medical Genetics · 2024Article
- Age and Sex Differences in the Genetics of Cardiomyopathy.Journal of cardiovascular translational research · 2023Article
- Genetic Determinants of the Interventricular Septum Are Linked to Ventricular Septal Defects and Hypertrophic Cardiomyopathy.Circulation. Genomic and precision medicine · 2023Article
- Molecular Diagnosis of Hypertrophic Cardiomyopathy (HCM): In the Heart of Cardiac Disease.Journal of clinical medicine · 2022Review
- European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases.Europace : European pacing, arrhythmias, and cardiac electrophysiology : journal of the working groups on cardiac pacing, arrhythmias, and cardiac cellular electrophysiology of the European Society of Cardiology · 2022Article
- European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) Expert Consensus Statement on the state of genetic testing for cardiac diseases.Journal of arrhythmia · 2022Article
- Rare and Common Genetic Variation Underlying the Risk of Hypertrophic Cardiomyopathy in a National Biobank.JAMA cardiology · 2022Article
- Minor hypertrophic cardiomyopathy genes, major insights into the genetics of cardiomyopathies.Nature reviews. Cardiology · 2022Review
- Inter-Species Rescue of Mutant Phenotype-The Standard for Genetic Analysis of Human Genetic Disorders inInternational journal of molecular sciences · 2022Review
- Protein Quality Control at the Sarcomere: Titin Protection and Turnover and Implications for Disease Development.Frontiers in physiology · 2022Review
- Deciphering pathogenicity of variants of uncertain significance with CRISPR-edited iPSCs.Trends in genetics : TIG · 2021Review
Corrections and comments
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Authors and funding
29 authors at 12 institutions in 2 countries.
Funding
Abstract
purposeIncreasing 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.
methodsUsing 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.
resultsWe 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.
conclusionFor 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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.