TY - JOUR T1 - Exome sequencing and genome-wide linkage analysis in 17 families illustrate the complex contribution of TTN truncating variants to dilated cardiomyopathy. JF - Circ Cardiovasc Genet Y1 - 2013 A1 - Norton, Nadine A1 - Li, Duanxiang A1 - Rampersaud, Evadnie A1 - Morales, Ana A1 - Martin, Eden R A1 - Zuchner, Stephan A1 - Guo, Shengru A1 - Gonzalez, Michael A1 - Hedges, Dale J A1 - Robertson, Peggy D A1 - Krumm, Niklas A1 - Nickerson, Deborah A A1 - Hershberger, Ray E KW - Adolescent KW - Adult KW - Aged KW - Cardiomyopathy, Dilated KW - Chromosomes, Human, Pair 9 KW - Connectin KW - Exome KW - Female KW - Genetic Heterogeneity KW - Genetic Linkage KW - Genetic Loci KW - Genome, Human KW - Humans KW - Male KW - Middle Aged KW - Muscle Proteins KW - Mutation, Missense KW - Odds Ratio KW - Pedigree KW - Protein Kinases KW - Sequence Analysis, DNA KW - Young Adult AB -

BACKGROUND- Familial dilated cardiomyopathy (DCM) is a genetically heterogeneous disease with >30 known genes. TTN truncating variants were recently implicated in a candidate gene study to cause 25% of familial and 18% of sporadic DCM cases. METHODS AND RESULTS- We used an unbiased genome-wide approach using both linkage analysis and variant filtering across the exome sequences of 48 individuals affected with DCM from 17 families to identify genetic cause. Linkage analysis ranked the TTN region as falling under the second highest genome-wide multipoint linkage peak, multipoint logarithm of odds, 1.59. We identified 6 TTN truncating variants carried by individuals affected with DCM in 7 of 17 DCM families (logarithm of odds, 2.99); 2 of these 7 families also had novel missense variants that segregated with disease. Two additional novel truncating TTN variants did not segregate with DCM. Nucleotide diversity at the TTN locus, including missense variants, was comparable with 5 other known DCM genes. The average number of missense variants in the exome sequences from the DCM cases or the ≈5400 cases from the Exome Sequencing Project was ≈23 per individual. The average number of TTN truncating variants in the Exome Sequencing Project was 0.014 per individual. We also identified a region (chr9q21.11-q22.31) with no known DCM genes with a maximum heterogeneity logarithm of odds score of 1.74. CONCLUSIONS- These data suggest that TTN truncating variants contribute to DCM cause. However, the lack of segregation of all identified TTN truncating variants illustrates the challenge of determining variant pathogenicity even with full exome sequencing.

VL - 6 IS - 2 U1 - http://www.ncbi.nlm.nih.gov/pubmed/23418287?dopt=Abstract ER -