title: New population-based exome data are questioning the pathogenicity of previously cardiomyopathy-associated genetic variants.
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.
authors.affiliation: The Danish National Research Foundation Centre for Cardiac Arrhythmia, Copenhagen, Denmark.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Andreasen
authors.forename: Jonas B
authors.initials: JB
authors.lastname: Nielsen
authors.forename: Lena
authors.initials: L
authors.lastname: Refsgaard
authors.forename: Anders G
authors.initials: AG
authors.lastname: Holst
authors.forename: Alex H
authors.initials: AH
authors.lastname: Christensen
authors.forename: Laura
authors.initials: L
authors.lastname: Andreasen
authors.forename: Ahmad
authors.initials: A
authors.lastname: Sajadieh
authors.forename: Stig
authors.initials: S
authors.lastname: Haunsø
authors.forename: Jesper H
authors.initials: JH
authors.lastname: Svendsen
authors.forename: Morten S
authors.initials: MS
authors.lastname: Olesen
mesh_terms: D009202:Cardiomyopathies / Q000235:genetics*; D016022:Case-Control Studies; D018389:Codon, Nonsense; D059472:Exome; D005189:False Positive Reactions; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D020125:Mutation, Missense; D017422:Sequence Analysis, DNA
chemical_list: D018389:Codon, Nonsense