Back to Search
Start Over
New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants
- Source :
- European Journal of Human Genetics
- Publication Year :
- 2013
- Publisher :
- Springer Science and Business Media LLC, 2013.
-
Abstract
- Cardiomyopathies are a heterogeneous group of diseases with various etiologies. We focused on three genetically determined cardiomyopathies: hypertrophic (HCM), dilated (DCM), and arrhythmogenic right ventricular cardiomyopathy (ARVC). Eighty-four genes have so far been associated with these cardiomyopathies, but the disease-causing effect of reported variants is often dubious. In order to identify possible false-positive variants, we investigated the prevalence of previously reported cardiomyopathy-associated variants in recently published exome data. We searched for reported missense and nonsense variants in the NHLBI-Go Exome Sequencing Project (ESP) containing exome data from 6500 individuals. In ESP, we identified 94 variants out of 687 (14%) variants previously associated with HCM, 58 out of 337 (17%) variants associated with DCM, and 38 variants out of 209 (18%) associated with ARVC. These findings correspond to a genotype prevalence of 1:4 for HCM, 1:6 for DCM, and 1:5 for ARVC. PolyPhen-2 predictions were conducted on all previously published cardiomyopathy-associated missense variants. We found significant overrepresentation of variants predicted as being benign among those present in ESP compared with the ones not present. In order to validate our findings, seven variants associated with cardiomyopathy were genotyped in a control population and this revealed frequencies comparable with the ones found in ESP. In conclusion, we identified genotype prevalences up to more than one thousand times higher than expected from the phenotype prevalences in the general population (HCM 1:500, DCM 1:2500, and ARVC 1:5000) and our data suggest that a high number of these variants are not monogenic causes of cardiomyopathy.
- Subjects :
- Genotype
Population
Mutation, Missense
Cardiomyopathy
Biology
Article
Gene Frequency
ARVC
Genetics
medicine
Humans
Missense mutation
Exome
False Positive Reactions
cardiovascular diseases
education
Allele frequency
Genetic Association Studies
Genetics (clinical)
Exome sequencing
DCM
education.field_of_study
Case-control study
High-Throughput Nucleotide Sequencing
Sequence Analysis, DNA
medicine.disease
HCM
Codon, Nonsense
Case-Control Studies
next-generation sequencing
Cardiomyopathies
cardiomyopathy
Subjects
Details
- ISSN :
- 14765438 and 10184813
- Volume :
- 21
- Database :
- OpenAIRE
- Journal :
- European Journal of Human Genetics
- Accession number :
- edsair.doi.dedup.....d328401de623e39009d137a493e7442c