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.

Determining pathogenicity of genetic variants in hypertrophic cardiomyopathy: importance of periodic reassessment

“…Most recently, up to 14% of all previously HCM-associated variants and 18% of all dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy-associated variants were reported to be present in ESP. 27 The 1000 Genomes database was also found to carry higher than expected prevalence of sarcomere gene mutations linked to HCM. 28 On the basis of the growth in available human genome data, coupled with increasing knowledge of disease mechanisms, and availability of newer in silico prediction programs, reevaluation of genetic findings over the last decade in clinical settings is of importance.…”

The landscape of genetic variation in dilated cardiomyopathy as surveyed by clinical DNA sequencing

“…This prevalence of historically misclassified pathogenic variation is consistent with a recent systematic reanalysis of putatively pathogenic cardiomyopathy variants in the NHLBI ESP cohort. 24 Of the 10 variants originally classified as "pathogenic, " only one was downgraded to "likely pathogenic. " The resultant number of variants assigned to each category was as follows: 376 "likely benign, " 374 of "unknown significance, " 43 "VUS-favor pathogenic, " 87 "likely pathogenic, " and 13 "pathogenic" (Supplementary Table S3 online).…”

“…18 The development and clinical performance characteristics of our NGS-based Pan Cardiomyopathy Panel are described in the Supplementary Data and Supplementary Table S6 online. In total, we analyzed 766 DCM cases using Sanger sequencing (176 cases), the DCM CardioChip microarray (417), NGS-based gene panels (149), or a combination of these (24). Patients who were tested more than once were counted toward the larger panel.…”

Analyses of more than 60,000 exomes questions the role of numerous genes previously associated with dilated cardiomyopathy

“…Interestingly, variants in TMPO and FLT1 have previously been identified numerously in a large control population (Andreasen et al. 2013). However, our study validates this in a control population ninefold larger.…”