Abstract 11221: Amino Acid-Level Signal-To-Noise Analysis of Rare Variants in the Troponin Complex Identifies “Hot Spots” Associated With Early Heart Failure, Increased Mortality, and Sudden Death

IntroductionCardiac troponins (Tn), including troponin T (TnT), I (TnI), and C (TnC) are critical for sensing calcium and triggering myocardial contraction. Tn mutations are associated with development of cardiomyopathy and heart failure (HF); however, recent advances in genetic analysis have identi...

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Published in:Circulation (New York, N.Y.) N.Y.), 2018-11, Vol.138 (Suppl_1 Suppl 1), p.A11221-A11221
Main Authors: Tadros, Hanna J, Life, Chelsea S, Garcia, Gustavo, Gong, Deshun, Parvatiyar, Michelle S, Allen, Hugh D, Kim, Jeff J, Yan, Nieng, Pinto, Jose R, Landstrom, Andrew P
Format: Article
Language:English
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Summary:IntroductionCardiac troponins (Tn), including troponin T (TnT), I (TnI), and C (TnC) are critical for sensing calcium and triggering myocardial contraction. Tn mutations are associated with development of cardiomyopathy and heart failure (HF); however, recent advances in genetic analysis have identified a number of rare variants found in healthy individuals. It is unclear how certain Tn variants are associated with disease while others are tolerated physiologically.HypothesisA novel amino acid level signal-to-noise (S:N) comparison of pathologic Tn variants with rare “healthy background” variation will define pathologic “hot spots” with diagnostic and prognostic relevance.MethodsCardiomyopathy-associated Tn variants were identified in the literature and topology mapping conducted (Ensembl). Among proband studies, clinical features were compiled (N= 84 studies, 229 probands). Rare variants in healthy individuals were collected from the GnomAD database (N=123136 exomes, MAF
ISSN:0009-7322
1524-4539