Abstract 15012: Role of Titin Gene Variants in Human Dilated Cardiomyopathy
Background: The Titin gene (TTN) is the second largest human gene and encodes the largest known human protein, titin, that plays a central role in sarcomere organization. Because of its large size, mutations in TTN have been difficult to study. Recent data have shown that truncation mutations in TTN can lead to a dilated cardiomyopathy phenotype. Titan’s large size means that almost all individuals carry missense TTN variants, the majority of which are presumably benign, and this raises challenges in the evaluation of TTN in patients with overt dilated cardiomyopathy.
Methods: Our group sequenced 313 exons covering the N2B and N2BA cardiac isoforms of TTN in 135 subjects with dilated cardiomyopathy. ‘Severe’ missense variants were identified by bioinformatic filtering based on SIFT score, GERP, Polyphen2 HDVAR, low frequency in the 1000 Genome Project, and NHLBI Exome Sequencing Project.
Results and Conclusions: Ultimately, 45 TTN ‘severe’ missense variants were noted in 38 probands. We were able to demonstrate segregation of ‘severe’ TTN missense variants in four larger families. Of the 38 probands, seven were compound TTN heterozygotes, and six were double heterozygotes with a ‘severe’ TTN variant and a pathogenic variant in another dilated cardiomyopathy gene. Genotype-Phenotype analyses between TTN ‘severe’ variant carriers and non-carriers was also performed which showed a trend towards better survival in TTN ‘severe’ missense carriers (p=0.071). These data provide important insight for researchers and laboratory into the prevalence and phenotypic consequences of ‘severe’ TTN variants in dilated cardiomyopathy patients.
- © 2013 by American Heart Association, Inc.