Genetic screening for mutations in patients with inherited cardiomyopathies using next generation sequencing -

Abstract

Cardiomyopathy is a disease affecting the myocardium leading to its weakness and enlargement, consequently ending in heart failure or sudden cardiac death. Cardiomyopathy is classified to five types based on its manifestation and morphological features: hypertrophic, dilated, restrictive left ventricular, arrhythmogenic right ventricular, and left ventricular non-compaction. A genetic component has been associated with the disease and linked to its risk factors. Recently, mutations in one of a panel of culprit genes identified so far classified cardiomyopathy as a hereditary disease. We have performed genetic screening for mutations in our populations, which have been only rarely studied, in a panel of the 34 genes implicated in cardiomyopathy phenotypes using Haloplex targeted next generation sequencing for 19 patients. We have used high throughput sequencing methods in which clonally amplified DNA templates of several cardiomyopathy patients were sequenced in a massively parallel fashion in a flow cell. Results have shown novel variants: TGβ3 (C409R) (K407R) (K407Q) and (E169D), DSP (E1181D) MYH7 (R1818L), DES (W295C), VCL (A259T), (R132L) and (R1055Q), ABCC9 (R661C), (V822E) and (R824P), RBM20 (R755C), MYBPC3 (S217G) and (G1249C), MYH6 (L772I) and (L1795M), JUP (T79P), MYl2 (P95T), TCAP (A164E), and finally TNNC1 (G70D). Among our results there were non-synonymous nonsense mutations that resulted in stop codons and were of clinical significance. These are TTN (S14991*), MYH6 (G1809*), and LDB3 (C444*) and one frame-shift deletion in MYH7 which resulted in alternative exon splicing. Seven patients, having idiopathic cardiomyopathy as the only cardiac disease, were whole-exome sequenced. We suspect to have three novel genes to be causing the cardiomyopathy disease: LARP6 and MYH15 both in a non-synonymous missense form and AR in a frame-shift form.Genetic population studies will help in finding an effective and well-organized genetic counseling plan combined with a deeper and richer understanding of the