Discovery of TITIN Gene Truncating Variant Mutations and 5-Year Outcomes in Patients With Nonischemic Dilated Cardiomyopathy

• Published in: The American journal of cardiology 2020-12, Vol.137, p.97-102
• Main Authors: Anderson, Jeffrey L., Christensen, G. Bryce, Escobar, Helaman, Horne, Benjamin D., Knight, Stacey, Jacobs, Victoria, Afshar, Kia, Hebl, Virginia B., Muhlestein, Joseph B., Knowlton, Kirk U., Carlquist, John F., Nadauld, Lincoln D.
• Format: Article
• Language: English
• Subjects: Cardiomyopathy; Cardiomyopathy, Dilated - genetics; Cardiomyopathy, Dilated - metabolism; Congestive heart failure; Connectin; Connectin - genetics; Connectin - metabolism; Deoxyribonucleic acid; Dilated cardiomyopathy; Disease; DNA; DNA - genetics; DNA Mutational Analysis; Electronic health records; Family medical history; Female; Follow-Up Studies; Genetic analysis; Genetic diversity; Genetic factors; Genetic variance; Genetic Variation; Genomes; Humans; Male; Medical records; Middle Aged; Mutation; Patients; Prognosis; Retrospective Studies; Risk analysis; Risk factors; Sequences; Time Factors; Transplants & implants; Ventricle
• ISSN: 0002-9149; 1879-1913
• DOI: 10.1016/j.amjcard.2020.09.026

•TTNtv mutations commonly cause NIDC, yet frequency and prognosis are uncertain.•Here we report discovery of 15 new TTNtv mutations associated with NIDC.•Outcome was worse at 5 years in carriers of known or new TTNtv mutations.•Environmental and disease cofactors frequently combine with TTNtv to precipitate NIDC. Genetic factors play an important role in nonischemic dilated cardiomyopathy (NIDC). However, prime opportunities remain for genetic discovery and prognostic understanding. TITIN gene truncating variant mutations (TTNtv) are of interest because of their frequent appearance in NIDC series. We sought to discover known and novel TTNtv mutations in a NIDC cohort and assess 5-year outcomes. Patients with NIDC entered into the INSPIRE Registry with ≥3 years of follow-up were studied. Whole exome sequencing (WES) was performed using an Illumina Novaseq platform. Genetic analysis used Sentieon software and the GRCh38 human reference genome. Variant calls were annotated with ClinVar. Five-year outcomes were determined by functional assessment and ejection fraction (EF) as recovered (EF ≥50%), persistent (EF 21% to 49%), or progressive (left ventricular assist device, transplant, heart failure [HF] or arrhythmic death, or EF ≤20%). The study comprised 229 NIDC patients (age = 50 ± 15 years, 58% men). TTNtv’s were discovered in 27 patients with 22 unique mutations; (7 known, 15 novel). TTNtv+ patients more frequently presented with severe NIDC (EF ≤20%) (p = 0.032). By 5-year, outcomes were worse in TTNtv+ patients (p = 0.027), and patients less often recovered (11% vs. 30%). Prognosis was similar with known and novel mutations. Nongenetic (e.g., environmental) cocausal risk factors for HF were frequently present, and these factors frequently appeared to act in concert with genetic variants to precipitate clinical HF. In conclusion, our study expands the library of likely pathogenic TTN mutations and increases our understanding of their clinical impact in association with other HF risk factors.