Open AccessRole of Titin Missense Variants in Dilated Cardiomyopathy
Author(s) -
Begay Rene L.,
Graw Sharon,
Sinagra Gianfranco,
Merlo Marco,
Slavov Dobromir,
Gowan Katherine,
Jones Kenneth L.,
Barbati Giulia,
Spezzacatene Anita,
Brun Francesca,
Di Lenarda Andrea,
Smith John E.,
Granzier Henk L.,
Mestroni Luisa,
Taylor Matthew
Publication year - 2015
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.115.002645
Subject(s) - missense mutation , titin , proband , dilated cardiomyopathy , genetics , medicine , cardiomyopathy , sarcomere , exon , gene , heterozygote advantage , mutation , genotype , biology , heart failure , myocyte
Background The titin gene ( TTN ) encodes the largest human protein, which plays a central role in sarcomere organization and passive myocyte stiffness. TTN truncating mutations cause dilated cardiomyopathy ( DCM ); however, the role of TTN missense variants in DCM has been difficult to elucidate because of the presence of background TTN variation. Methods and Results A cohort of 147 DCM index subjects underwent DNA sequencing for 313 TTN exons covering the N2B and N2 BA cardiac isoforms of TTN . Of the 348 missense variants, we identified 44 “severe” rare variants by using a bioinformatic filtering process in 37 probands. Of these, 5 probands were double heterozygotes (additional variant in another DCM gene) and 7 were compound heterozygotes (2 TTN “severe” variants). Segregation analysis allowed the classification of the “severe” variants into 5 “likely” (cosegregating), 5 “unlikely” (noncosegregating), and 34 “possibly” (where family structure precluded segregation analysis) disease‐causing variants. Patients with DCM carrying “likely” or “possibly” pathogenic TTN “severe” variants did not show a different outcome compared with “unlikely” and noncarriers of a “severe” TTN variant. However, the “likely” and “possibly” disease‐causing variants were overrepresented in the C‐zone of the A‐band region of the sarcomere. Conclusions TTN missense variants are common and present a challenge for bioinformatic classification, especially when informative families are not available. Although DCM patients carrying bioinformatically “severe” TTN variants do not appear to have a worse clinical course than noncarriers, the nonrandom distribution of “likely” and “possibly” disease‐causing variants suggests a potential biological role for some TTN missense variants.