Smidt Heart Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd, Los Angeles, CA, 90048, USA.
Department of Cardiovascular Medicine, Nippon Medical School Graduate School, Tokyo, Japan.
ESC Heart Fail. 2021 Dec;8(6):5178-5191. doi: 10.1002/ehf2.13596. Epub 2021 Sep 6.
The aim of the present study was to consider whether the ultrastructural features of cardiomyocytes in dilated cardiomyopathy can be used to guide genetic testing.
Endomyocardial biopsy and whole-exome sequencing were performed in 32 consecutive sporadic dilated cardiomyopathy patients [51.0 (40.0-64.0) years, 75% men] in initial phases of decompensated heart failure. The predicted pathogenicity of ultrarare (minor allele frequency ≤0.0005), non-synonymous variants was determined using the American College of Medical Genetics guidelines. Focusing on 75 cardiomyopathy-susceptibility and 41 arrhythmia-susceptibility genes, we identified 404 gene variants, of which 15 were considered pathogenic or likely pathogenic in 14 patients (44% of 32). There were five sarcomeric gene variants (29% of 17 variants) found in five patients (16% of 32), involving a variant of MYBPC3 and four variants of TTN. A patient with an MYBPC3 variant showed disorganized sarcomeres, three patients with TTN variants located in the region encoding the A-band domain showed sparse sarcomeres, and a patient with a TTN variant in encoding the I-band domain showed disrupted sarcomeres. The distribution of diffuse myofilament lysis depended on the causal genes; three patients with the same TMEM43 variant had diffuse myofilament lysis near nuclei (P = 0.011), while two patients with different DSP variants had lysis in the peripheral areas of cardiomyocytes (P = 0.033).
Derangement patterns of myofilament and subcellular distribution of myofilament lysis might implicate causal genes. Large-scale studies are required to confirm whether these ultrastructural findings are related to the causative genes.
本研究旨在探讨扩张型心肌病（Dilated cardiomyopathy，DCM）患者心肌细胞的超微结构特征是否可用于指导基因检测。
对 32 例处于失代偿心力衰竭早期的散发性扩张型心肌病患者（51.0（40.0-64.0）岁，75%为男性）进行心内膜心肌活检和全外显子组测序。使用美国医学遗传学学院指南确定超罕见（次要等位基因频率≤0.0005）、非同义变异的致病性预测。研究聚焦于 75 个心肌病易感性和 41 个心律失常易感性基因，共鉴定出 404 个基因变异，其中 14 例患者的 15 个变异被认为具有致病性或可能致病性（32 例患者的 44%）。在 5 例患者（32 例患者的 16%）中发现了 5 个肌节基因变异（17 个变异的 29%），包括 MYBPC3 的一个变异和 TTN 的四个变异。1 例 MYBPC3 变异患者的肌节排列紊乱，3 例 TTN 变异位于编码 A 带区的患者的肌节稀疏，1 例编码 I 带区的 TTN 变异患者的肌节破坏。弥漫性肌丝溶解的分布取决于致病基因；3 例携带相同 TMEM43 变异的患者核旁有弥漫性肌丝溶解（P=0.011），而 2 例携带不同 DSP 变异的患者在心肌细胞的周边区域有肌丝溶解（P=0.033）。
肌丝排列紊乱和肌丝溶解的亚细胞分布模式可能提示致病基因。需要进行大规模研究以确认这些超微结构发现是否与致病基因有关。
