Abstract
The cardiac troponin T variations have often been used as an example of the application of clinical genotyping for prognostication and risk stratification measures for the management of patients with a family history of sudden cardiac death or familial cardiomyopathy. Given the disparity in patient outcomes and therapy options, we investigated the impact of variations on the intermolecular interactions across the thin filament complex as an example of an unbiased systems biology method to better define clinical prognosis to aid future management options. We present a novel unbiased dynamic model to define and analyse the functional, structural and physico-chemical consequences of genetic variations among the troponins. This was subsequently integrated with clinical data from accessible global multi-centre systematic reviews of familial cardiomyopathy cases from 106 articles of the literature: 136 disease-causing variations pertaining to 981 global clinical cases. Troponin T variations showed distinct pathogenic hotspots for dilated and hypertrophic cardiomyopathies; considering the causes of cardiovascular death separately, there was a worse survival in terms of sudden cardiac death for patients with a variation at regions 90–129 and 130–179 when compared to amino acids 1–89 and 200–288. Our data support variations among 90–130 as being a hotspot for sudden cardiac death and the region 131–179 for heart failure death/transplantation outcomes wherein the most common phenotype was dilated cardiomyopathy. Survival analysis into regions of high risk (regions 90–129 and 130–180) and low risk (regions 1–89 and 200–288) was significant for sudden cardiac death (p = 0.011) and for heart failure death/transplant (p = 0.028). Our integrative genomic, structural, model from genotype to clinical data integration has implications for enhancing clinical genomics methodologies to improve risk stratification.
Highlights
IntroductionThe most common forms of genetic heart disease are the inherited cardiomyopathies, which affect ~0.2% of the global population[1,2]
The most common forms of genetic heart disease are the inherited cardiomyopathies, which affect ~0.2% of the global population[1,2].The cardiomyopathies are a group of rare heart muscle disorders that afflict the structure and physiological function of the myocardium
The static amino acid interactions between subunits are independent of calcium binding, while dynamic interactions depend upon calcium binding (Fig. 1)
Summary
The most common forms of genetic heart disease are the inherited cardiomyopathies, which affect ~0.2% of the global population[1,2]. The cardiomyopathies are a group of rare heart muscle disorders that afflict the structure and physiological function of the myocardium. The two most common traditional pathological forms are dilated and hypertrophic cardiomyopathies, each with characteristic clinical phenotypes and often showing an autosomal dominant inheritance. The most common genetic variations appear in sarcomeric proteins; of which the troponin (Tn) proteins are part of the larger thin filament complex within the regulatory unit of the sarcomere. The Tn variations are thought to contribute approximately to 8–10% of all the known sarcomeric protein cardiomyopathies[3]. Given the lack of a complete Tn complex, analysis has often been limited to sub-complexes
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
