Meta-analysis of cardiomyopathy-associated variants in troponin genes identifies loci and intragenic hot spots that are associated with worse clinical outcomes.
Abstract
INTRODUCTION:Troponin (TNN)-encoded cardiac troponins (Tn) are critical for sensing
calcium and triggering myofilament contraction. TNN variants are associated with development
of cardiomyopathy; however, recent advances in genetic analysis have identified rare
population variants. It is unclear how certain variants are associated with disease
while others are tolerated. OBJECTIVE:To compare probands with TNNT2, TNNI3, and TNNC1
variants and utilize high-resolution variant comparison mapping of pathologic and
rare population variants to identify loci associated with disease pathogenesis. METHODS:Cardiomyopathy-associated
TNN variants were identified in the literature and topology mapping conducted. Clinical
features were compiled and compared. Rare population variants were obtained from the
gnomAD database. Signal-to-noise (S:N) normalized pathologic variant frequency against
population variant frequency. Abstract review of clinical phenotypes was applied to
"significant" hot spots. RESULTS:Probands were compiled (N = 70 studies, 224 probands)
as were rare variants (N = 125,748 exomes; 15,708 genomes, MAF <0.001). TNNC1-positive
probands demonstrated the youngest age of presentation (20.0 years; P = .016 vs TNNT2;
P = .004 vs TNNI3) and the highest death, transplant, or ventricular fibrillation
events (P = .093 vs TNNT2; P = .024 vs TNNI3; Kaplan Meir: P = .025). S:N analysis
yielded hot spots of diagnostic significance within the tropomyosin-binding domains,
α-helix 1, and the N-Terminus in TNNT2 with increased sudden cardiac death and ventricular
fibrillation (P = .004). The inhibitory region and C-terminal region in TNNI3 exhibited
increased restrictive cardiomyopathy (P =.008). HCM and RCM models tended to have
increased calcium sensitivity and DCM decreased sensitivity (P < .001). DCM and HCM
studies typically showed no differences in Hill coefficient which was decreased in
RCM models (P < .001). CM models typically demonstrated no changes to Fmax (P = .239).
CONCLUSION:TNNC1-positive probands had younger ages of diagnosis and poorer clinical
outcomes. Mapping of TNN variants identified locations in TNNT2 and TNNI3 associated
with heightened pathogenicity, RCM diagnosis, and increased risk of sudden death.
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https://hdl.handle.net/10161/21938Published Version (Please cite this version)
10.1016/j.yjmcc.2020.04.005Publication Info
Tadros, Hanna J; Life, Chelsea S; Garcia, Gustavo; Pirozzi, Elisa; Jones, Edward G;
Datta, Susmita; ... Landstrom, Andrew P (2020). Meta-analysis of cardiomyopathy-associated variants in troponin genes identifies loci
and intragenic hot spots that are associated with worse clinical outcomes. Journal of molecular and cellular cardiology, 142. pp. 118-125. 10.1016/j.yjmcc.2020.04.005. Retrieved from https://hdl.handle.net/10161/21938.This is constructed from limited available data and may be imprecise. To cite this
article, please review & use the official citation provided by the journal.
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Show full item recordScholars@Duke
Andrew Paul Landstrom
Associate Professor of Pediatrics
Dr. Landstrom is a physician scientist who specializes in the care of children and
young adults with arrhythmias, heritable cardiovascular diseases, and sudden unexplained
death syndromes. As a clinician, he is trained in pediatric cardiology with a focus
on arrhythmias and genetic diseases of the heart. He specializes in caring for patients
with heritable arrhythmia (channelopathies) such as long QT syndrome, Brugada syndrome,
catecholaminergic polymorphic ventricular tachycardia,

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