ArticleCirculation. Cardiovascular genetics2012
Cardiac structural and sarcomere genes associated with cardiomyopathy exhibit marked intolerance of genetic variation.
Article in Circulation. Cardiovascular genetics, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 34 papers, 1 of them a synthesis that pooled it.
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Who cites it
34 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Genetic evaluation of cardiomyopathy: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG).Genetics in medicine : official journal of the American College of Medical Genetics · 2018Guideline
- Identification of candidate cardiomyopathy modifier genes through genome sequencing and RNA profiling.Frontiers in cardiovascular medicine · 2025Article
- The Genetic Factors Influencing Cardiomyopathies and Heart Failure across the Allele Frequency Spectrum.Journal of cardiovascular translational research · 2024Review
- Dynamics of the Pre-Powerstroke Myosin Lever Arm and the Effects of Omecamtiv Mecarbil.International journal of molecular sciences · 2024Article
- Genotype-Phenotype Insights of Inherited Cardiomyopathies-A Review.Medicina (Kaunas, Lithuania) · 2024Review
- Hypoxia Attenuates Pressure Overload-Induced Heart Failure.Journal of the American Heart Association · 2024Article
- Serine biosynthesis as a novel therapeutic target for dilated cardiomyopathy.European heart journal · 2022Article
- Promise and Peril of Population Genomics for the Development of Genome-First Approaches in Mendelian Cardiovascular Disease.Circulation. Genomic and precision medicine · 2021Review
- Prospective Evaluation of the Utility of Whole Exome Sequencing in Dilated Cardiomyopathy.Journal of the American Heart Association · 2020Article
- A study of the pathogenicity of variants in familial heart disease. The value of cosegregation.American journal of translational research · 2019Article
- A gene-centric strategy for identifying disease-causing rare variants in dilated cardiomyopathy.Genetics in medicine : official journal of the American College of Medical Genetics · 2019Article
- Genetic Evaluation of Cardiomyopathy-A Heart Failure Society of America Practice Guideline.Journal of cardiac failure · 2018Review
- Clinical and Mechanistic Insights Into the Genetics of Cardiomyopathy.Journal of the American College of Cardiology · 2016Review
- Update on hypertrophic cardiomyopathy and a guide to the guidelines.Nature reviews. Cardiology · 2016Review
- Multidimensional structure-function relationships in human β-cardiac myosin from population-scale genetic variation.Proceedings of the National Academy of Sciences of the United States of America · 2016Article
- The Role of Genetic Testing in the Identification of Young Athletes with Inherited Primitive Cardiac Disorders at Risk of Exercise Sudden Death.Frontiers in cardiovascular medicine · 2016Review
- Recent Advances in the Molecular Genetics of Familial Hypertrophic Cardiomyopathy in South Asian Descendants.Frontiers in physiology · 2016Review
- Establishing disease causality for a novel gene variant in familial dilated cardiomyopathy using a functional in-vitro assay of regulated thin filaments and human cardiac myosin.BMC medical genetics · 2015Article
- Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios.Genetics in medicine : official journal of the American College of Medical Genetics · 2015Article
- New approaches to establish genetic causality.Trends in cardiovascular medicine · 2015Review
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Abstract
backgroundThe clinical significance of variants in genes associated with inherited cardiomyopathies can be difficult to determine because of uncertainty regarding population genetic variation and a surprising amount of tolerance of the genome even to loss-of-function variants. We hypothesized that genes associated with cardiomyopathy might be particularly resistant to the accumulation of genetic variation. METHODS AND
resultsWe analyzed the rates of single nucleotide genetic variation in all known genes from the exomes of >5000 individuals from the National Heart, Lung, and Blood Institute's Exome Sequencing Project, as well as the rates of structural variation from the Database of Genomic Variants. Most variants were rare, with over half unique to 1 individual. Cardiomyopathy-associated genes exhibited a rate of nonsense variants, about 96.1% lower than other Mendelian disease genes. We tested the ability of in silico algorithms to distinguish between a set of variants in MYBPC3, MYH7, and TNNT2 with strong evidence for pathogenicity and variants from the Exome Sequencing Project data. Algorithms based on conservation at the nucleotide level (genomic evolutionary rate profiling, PhastCons) did not perform as well as amino acid-level prediction algorithms (Polyphen-2, SIFT). Variants with strong evidence for disease causality were found in the Exome Sequencing Project data at prevalence higher than expected.
conclusionsGenes associated with cardiomyopathy carry very low rates of population variation. The existence in population data of variants with strong evidence for pathogenicity suggests that even for Mendelian disease genetics, a probabilistic weighting of multiple variants may be preferred over the single gene causality model.
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