Genetic epidemiology of titin-truncating variants in the etiology of dilated cardiomyopathy

Biophys Rev Genetic epidemiology of titin-truncating variants in the etiology of dilated cardiomyopathy Ali M. Tabish 0 1 2 Ralph Knöll 0 1 2 Valerio Azzimato 0 1 2 Aris Alexiadis 0 1 2 Byambajav Buyandelger 0 1 2 0 AstraZeneca R&D Mölndal, R&D, Innovative Medicines & Early Development, Cardiovascular & Metabolic Diseases iMed , 431 83 Mölndal , Sweden 1 Integrated Cardio Metabolic Centre (ICMC), Karolinska Institutet , 141 57 Huddinge , Sweden 2 Ali M. Tabish Heart failure (HF) is a complex clinical syndrome defined by the inability of the heart to pump enough blood to meet the body's metabolic demands. Major causes of HF are cardiomyopathies (diseases of the myocardium associated with mechanical and/or electrical dysfunction), among which the most common form is dilated cardiomyopathy (DCM). DCM is defined by ventricular chamber enlargement and systolic dysfunction with normal left ventricular wall thickness, which leads to progressive HF. Over 60 genes are linked to the etiology of DCM. Titin (TTN) is the largest known protein in biology, spanning half the cardiac sarcomere and, as such, is a basic structural and functional unit of striated muscles. It is essential for heart development as well as mechanical and regulatory functions of the sarcomere. Next-generation sequencing (NGS) in clinical DCM cohorts implicated truncating variants in titin (TTNtv) as major disease alleles, accounting for more than 25% of familial DCM cases, but these variants have also been identified in 2-3% of the general population, where these TTNtv blur diagnostic and clinical utility. Taking into account the published TTNtv and their association to DCM, it becomes clear that TTNtv harm the heart with Titin; Heart failure; Dilated cardiomyopathy; Epidemiology; Truncating variants - position-dependent occurrence, being more harmful when present in the A-band TTN, presumably with dominant negative/gain-of-function mechanisms. However, these insights are challenged by the depiction of position-independent toxicity of TTNtv acting via haploinsufficient alleles, which are sufficient to induce cardiac pathology upon stress. In the current review, we provide an overview of TTN and discuss studies investigating various TTN mutations. We also present an overview of different mechanisms postulated or experimentally validated in the pathogenicity of TTNtv. DCMcausing genes are also discussed with respect to nontruncating mutations in the etiology of DCM. One way of understanding pathogenic variants is probably to understand the context in which they may or may not affect protein–protein interactions, changes in cell signaling, and substrate specificity. In this regard, we also provide a brief overview of TTN interactions in situ. Quantitative models in the risk assessment of TTNtv are also discussed. In summary, we highlight the importance of gene–environment interactions in the etiology of DCM and further mechanistic studies used to delineate the pathways which could be targeted in the management of DCM. Abbreviations Crispr Clustered regularly interspaced short palindromic repeats CVD Cardiovascular disease DCM Dilated cardiomyopathy ExAC Exome Aggregation Consortium eGFP Enhanced green fluorescent protein ENU Ethylnitrosourea FINmaj Finnish founder mutation GWAS HCM HF LV NGS NMD PEVK TTN TTNtv TTNtvA TTNtvZ Genome-wide association studies Hypertrophic cardiomyopathy Heart failure Left ventricle Next-generation sequencing Nonsense-mediated mRNA decay Pro-Glu-Val-Lys titin domain Titin Titin-truncating variants TTNtv at the A-band titin TTNtv at Z-disk titin Introduction Heart failure (HF) is a complex clinical syndrome which concerns the impaired ability of the heart to pump and/or fill with blood, resulting in inadequate cardiac output to meet metabolic demands or, more commonly, adequate cardiac output but only due to compensatory neurohormonal activation (Mann and Bristow 2005) . The prevalence of HF in the general population is high (1–1.5%) and morbidity and mortality is among the highest of any disease or disease syndromes (Ho et al. 1993; Roger 2013) . HF is probably best understood from the vantage point of cardiomyopathies. Cardiomyopathies are a heterogeneous group of diseases of the myocardium associated with mechanical and/or electrical dysfunction that usually exhibit inappropriate ventricular hypertrophy or dilatation, with frequently occurring underlying genetic causes (Maron et al. 2006) . Cardiomyopathies are classified into primary and secondary cardiomyopathies. Primary cardiomyopathies are based on the exclusion of secondary cardiomyopathies, and include several clinical types, of which the most common is dilated cardiomyopathy (DCM), which is characterized by ventricular chamber enlargement and systolic dysfunction with normal left ventricular wall thickness, leading to progressive HF and a decline in left ventricle (LV) contractile function, ventricular and supraventricular arrhythmias, thr (...truncated)