Meta-analysis of cardiomyopathy-associated variants in troponin genes identifies loci and intragenic hot spots that are associated with worse clinical outcomes.


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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Publication Info

Tadros, Hanna J, Chelsea S Life, Gustavo Garcia, Elisa Pirozzi, Edward G Jones, Susmita Datta, Michelle S Parvatiyar, P Bryant Chase, et al. (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

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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, and short QT syndrome.  He also specializes in the evaluation of children following a cardiac arrest or after the sudden and unexplained death of a family member.  He has expertise in cardiovascular genetics and uses it to identify individuals in a family who may be at risk of a disease, even if all clinical testing is negative.  As a scientist, he is trained in genetics and cell biology.  He runs a research lab exploring the genetic and molecular causes of arrhythmias, sudden unexplained death syndromes, and heart muscle disease (cardiomyopathies).  He utilizes patient-derived induced pluripotent stem cells and genetic mouse models to identify the mechanisms of cardiovascular genetic disease with the goal of developing novel therapies.

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