Truncating Titin Variants Clause Samples

Truncating Titin Variants. The largest human protein, titin is encoded by the titin (TTN) gene, expressed in the heart and has an important scaffolding role within the sarcomere in providing the resting tension and physiological stiffness, necessary for structural integrity (148). TTNtv, in an autosomal dominant fashion, contributes the most cases towards genetic DCM, accounting for approximately 15-25% of the burden (148). Whilst the functional phenotype of DCM due to TTNtv appears similar in terms of LV dimensions and ejection fraction at diagnosis to DCM in the absence of TTNtv, there is increasing evidence supporting an early arrhythmic predisposition for those with TTNtv-DCM (149). Interestingly, this tendency has not been demonstrated to influence an increased number of adverse cardiac outcomes nor does it appear to impact the potential for the LV to reverse remodel with medical therapy (149,150). In some subsets, there is additionally an important relationship with non-genetic modifiers, with some evidence that carriers of TTNtv are more likely to develop the DCM phenotype in the presence of superadded environmental factors or situations such as chemotherapy, pregnancy and some toxic cardiomyopathies (66,67). Further understanding in this arena of gene-environment interaction will have important implications in counselling, lifestyle modifications and therapeutic considerations, that may modify risk.