| Summary: | Non ischaemic dilated cardiomyopathy (DCM) is an important cause of heart failure leading to chronic morbidity and death and as such is a major health burden. DCM is familial in up to 50% of cases but is genetically heterogeneous, hindering both genotype-phenotype studies and the application of genetic information for stratified patient management. TTN truncating variants (TTNtv) cause severe and familial DCM, but sometimes occur in healthy individuals, posing challenges for the interpretation of these variants. In this PhD thesis, the power of quantitative cardiac MRI (CMR) is integrated with targeted resequencing of TTN in order to assess the relationship between TTN genotype, cardiac phenotype and clinical outcomes. A prospectively recruited DCM cohort was established following CMR assessment in 374 patients (88% Caucasian, 72% male, mean age 54 ± 35 years, mean left ventricular ejection fraction (LVEF) 38% ± 24.5%, mean indexed end-diastolic volume 129 ± 141 mm). Following several iterations of design, refinement and testing an NGS assay was produced that captures all TTN coding exons and splice sites. Optimal parameters for sequencing and analysis of variants were established and genotype data compiled from 374 prospective, unselected cases, 155 end-stage retrospective cases, and 308 MRI phenotyped healthy volunteers. These data were integrated with that from 3603 population subjects and together used to identify molecular signatures that aid interpretation of TTN truncations both in DCM and as incidental findings. Overall, TTNtv were identified in 1.4% of controls, 13% of unselected and 22% of end-stage DCM cases (OR = 13, P= 2.8x10-43, DCM vs controls) confirming TTN as the commonest cause of genetic DCM in all patient groups. TTNtv-containing exons in DCM have higher usage than those in controls (P=2.5x10-4) and these are estimated to have >93% probability of pathogenicity (likelihood ratio 14). Compared to TTNtv-ve DCM, TTNtv+ve patients had lower LVEF (P=0.02), thinner LV walls (P=0.02), and a higher incidence of sustained ventricular tachycardia (P=0.001). C-terminus TTNtv were also associated with lower LVEF versus N-terminus (β=-18±7%, p=0.006) and were more common in end-stage disease. Together these data provide the first insight into genotype-phenotype correlations and will be of benefit in variant interpretation and patient stratification in TTN-based DCM.
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