Abstract 10660: Comparison Between Ultrastructural Features and Causative Genes of Dilated Cardiomyopathy Detected by Whole Exome Sequencing

IntroductionElectron microscopy for endomyocardial biopsy (EMB) samples allows detailed analysis for degeneration of cardiomyocytes. Myofilament changes in cardiomyocytes can predict poor prognosis of dilated cardiomyopathy (DCM). Research on causative genes of several diseases, including DCM, by next-generation sequencing (NGS) has been remarkable. However, ultrastructural findings of cardiomyocytes corresponding to each genetic variant in DCM patients has not been studied thoroughly.HypothesisUltrastructural findings correlate with the causative genes of DCM detected by whole-exome sequencing (WES) using NGS.MethodsEMB from the left ventricle (LV) and WES (Agilent SureSelect Human All Exon V6) were performed in 32 consecutive DCM patients (52.9±13.0 years, 75% men). A WES of 104 cardiomyopathy and arrhythmia-susceptibility genes was performed. The predicted pathogenicity of ultrarare (minor allele frequency ≤0.0005 in Exome Aggregation Consortium [n=60706] and 1000 Genome Project [n=1094]), nonsynonymous variants was determined using the American College of Medical Genetics (ACMG) guidelines, comparing with findings of electron microscopy.ResultsFifty-eight variants were identified, and 18 were considered pathogenic or likely pathogenic in 17 (53% of 32) patients with DCM in accordance with the ACMG guidelines. Pathogenic or likely pathogenic variants were divided according to whether the variant involved a sarcomere gene; six (33% of 18) sarcomeric gene variants were present in six (19% of 32) patients and 12 (67% of 18) non-sarcomeric genes were present in 13 (41% of 32) patients. Sarcomeric gene variants involved MYBPC3, NEXN, and TTN. Electron microscopy revealed that ultrastructural findings differed depending on the causative gene. A patient with variant of MYBPC3 showed fraying sarcomeres; a patient with variant of NEXN showed disruption Z-bands; and four patients with variants of TTN exhibited sparse sarcomeres. The non-sarcomeric gene group commonly exhibited diffuse myofilament lysis, reported as a poor prognostic factor (62% vs. 21% in the sarcomeric gene group, P=0.025).ConclusionsElectron microscopy is effective for evaluation of causative genes of DCM.