Abstract 13359: Exome Sequencing and Genome-Wide Linkage Analysis in 17 Families with Dilated Cardiomyopathy Confirms TTN Truncating Variants as a Major Cause
Background: Dilated cardiomyopathy (DCM) is a genetically heterogeneous disease with >30 known genes accounting for ∼50% of cause, of which TTN truncating variants were recently implicated in a candidate gene study to cause 25% of familial and 18% of sporadic DCM cases. In that study 3% of controls carried truncating variants.
Methods: To identify genetic cause in 17 families where mutations had previously been excluded in 16 known DCM genes, we used an unbiased genome-wide approach with two-point and multipoint parametric linkage analysis and variant filtering across the exome sequences of 48 individuals affected with DCM. Filtering included: missense, nonsense, splice site, or coding indel variants shared across affected members of a family; frequency <0.5% in 5,400 exome sequences from the Exome Variation Server (EVS); either a Phastcons score >0.4 or a GERP score >2; myocardial gene expression in our in-house transcriptome dataset of RPKM>3.
Results: Linkage analysis ranked the TTN region as falling under the second highest genome-wide multipoint linkage peak, MLOD 1.9. We identified six TTN truncating variants in 7 of 17 (41%) DCM families (LOD 3.54), 5 of which were considered likely to be disease causing, one possibly disease causing. Two other non-segregating TTN truncating variants, and 2 other segregating missense variants, none of which were in the EVS, were considered of unknown significance or as potentially disease-related, respectively. To gain greater insight into TTN nucleotide diversity, we compared its diversity to 5 other DCM genes, and found it comparable. Missense variants in the exome sequences from DCM cases or the ∼5,400 cases from the EVS averaged ∼23 per individual; TTN truncating variants in the EVS averaged 0.014 per individual. We also identified a region (chr9q21.11-q22.31) with a maximum heterogeneity LOD score of 3.14; none of the top ranking genes from our rare variant exome analysis or from known DCM genes mapped to this region.
Conclusion: These data show TTN truncating variants as a frequent cause of DCM using unbiased genome-wide analyses; the 41% frequency in these 17 families likely resulted from a DCM cohort depleted of other known genetic cause and thus enriched for TTN truncating variants.
- © 2012 by American Heart Association, Inc.