State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.
Beijing Key Laboratory of Preclinical Research and Evaluation for Cardiovascular Implant Materials, Animal Experimental Center, Fuwai Hospital, National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, China.
J Transl Med. 2023 Jul 17;21(1):476. doi: 10.1186/s12967-023-04282-5.
Dilated cardiomyopathy (DCM) is one of the most frequent causes of heart failure and heart transplantation (HTx). The genetic basis of DCM among patients undergoing HTx remains to be further studied. This study aimed to characterize the genetic basis of DCM HTx in the Chinese population.
In total, 208 unrelated DCM patients who underwent HTx at Fuwai Hospital between June 2004 and June 2017 were included in this study. Whole-exome sequencing (WES) was performed for all patients. Gene burden analysis, variant classification, and genotype-phenotype correlation analysis were subsequently performed.
After completing the bioinformatics analysis, gene burden analysis suggested that titin (TTN), filamin C (FLNC) and lamin A/C (LMNA) were significantly enriched with rare protein-altering variants. The frequencies of TTN and FLNC truncating variants in our cohort were 18.8% and 8.7%, respectively. Among the 165 rare variants in high evidence DCM-related genes, 27 (16.4%) and 59 (35.8%) were interpreted as pathogenic (P) and likely pathogenic (LP), respectively. In addition, 41 (47.7%) and 16 (18.6%) of these 86 P/LP variants are located in TTN and FLNC, respectively. The FLNC group contained more patients with NYHA class IV than the P/LP-negative group (FLNC, 16/18 vs. P/LP-negative, 81/123, P = 0.049).
Based on WES, we provided a primary genetic spectrum of DCM patients undergoing HTx in the Chinese population. TTN and FLNC harbour the most P/LP variants. FLNC truncation may lead to severe clinical symptoms in DCM patients.
扩张型心肌病（DCM）是心力衰竭和心脏移植（HTx）最常见的原因之一。接受 HTx 的 DCM 患者的遗传基础仍需进一步研究。本研究旨在描述中国人群 HTx 后 DCM 的遗传基础。
本研究共纳入 208 例 2004 年 6 月至 2017 年 6 月期间在阜外医院接受 HTx 的 DCM 患者。对所有患者进行全外显子组测序（WES）。随后进行基因负担分析、变异分类和基因型-表型相关性分析。
完成生物信息学分析后，基因负担分析表明，肌联蛋白（TTN）、原肌球蛋白 C（FLNC）和核纤层蛋白 A/C（LMNA）显著富集了罕见的蛋白改变变异。在我们的队列中，TTN 和 FLNC 截断变异的频率分别为 18.8%和 8.7%。在 165 个高证据 DCM 相关基因中的罕见变异中，27 个（16.4%）和 59 个（35.8%）被解释为致病性（P）和可能致病性（LP）。此外，这 86 个 P/LP 变异中有 41 个（47.7%）和 16 个（18.6%）位于 TTN 和 FLNC 中。FLNC 组 NYHA 心功能分级 IV 级的患者多于 P/LP 阴性组（FLNC，16/18 比 P/LP 阴性，81/123，P=0.049）。
基于 WES，我们提供了中国人群 HTx 后 DCM 患者的主要遗传谱。TTN 和 FLNC 携带最多的 P/LP 变异。FLNC 截断可能导致 DCM 患者出现严重的临床症状。
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