Coenzyme Q deficiency may predispose to sudden unexplained death via an increased risk of cardiac arrhythmia.

IF 2.2 3区 医学 Q1 MEDICINE, LEGAL
International Journal of Legal Medicine Pub Date : 2024-11-01 Epub Date: 2024-06-07 DOI:10.1007/s00414-024-03265-5
Shouyu Wang, Cordula Haas, Zhimin Wang, Jianghua Du, Zijie Lin, Guanghui Hong, Liliang Li, Ruiyang Tao, Yiwen Shen, Jacqueline Neubauer
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Abstract

Cardiac arrhythmia is currently considered to be the direct cause of death in a majority of sudden unexplained death (SUD) cases, yet the genetic predisposition and corresponding endophenotypes contributing to SUD remain incompletely understood. In this study, we aimed to investigate the involvement of Coenzyme Q (CoQ) deficiency in SUD. First, we re-analyzed the exome sequencing data of 45 SUD and 151 sudden infant death syndrome (SIDS) cases from our previous studies, focusing on previously overlooked genetic variants in 44 human CoQ deficiency-related genes. A considerable proportion of the SUD (38%) and SIDS (37%) cases were found to harbor rare variants with likely functional effects. Subsequent burden testing, including all rare exonic and untranslated region variants identified in our case cohorts, further confirmed the existence of significant genetic burden. Based on the genetic findings, the influence of CoQ deficiency on electrophysiological and morphological properties was further examined in a mouse model. A significantly prolonged PR interval and an increased occurrence of atrioventricular block were observed in the 4-nitrobenzoate induced CoQ deficiency mouse group, suggesting that CoQ deficiency may predispose individuals to sudden death through an increased risk of cardiac arrhythmia. Overall, our findings suggest that CoQ deficiency-related genes should also be considered in the molecular autopsy of SUD.

Abstract Image

缺乏辅酶Q可能会增加心律失常的风险,从而导致不明原因的猝死。
目前,心律失常被认为是大多数不明原因猝死(SUD)病例的直接死因,但导致SUD的遗传易感性和相应的内表型仍不完全清楚。本研究旨在探讨辅酶Q(CoQ)缺乏与不明原因猝死的关系。首先,我们重新分析了之前研究中45例SUD和151例婴儿猝死综合征(SIDS)病例的外显子组测序数据,重点研究了44个人类辅酶Q缺乏相关基因中之前被忽视的遗传变异。结果发现,相当大比例的 SUD(38%)和 SIDS(37%)病例携带有可能具有功能影响的罕见变异。随后进行的负荷测试(包括在我们的病例队列中发现的所有罕见外显子和非翻译区变异)进一步证实了重大遗传负荷的存在。根据基因研究结果,我们在小鼠模型中进一步研究了 CoQ 缺乏对电生理和形态学特性的影响。在4-硝基苯甲酸盐诱导的CoQ缺乏小鼠组中,观察到PR间期明显延长,房室传导阻滞的发生率增加,这表明CoQ缺乏可能会增加心律失常的风险,从而导致猝死。总之,我们的研究结果表明,在对猝死症进行分子解剖时,还应考虑与 CoQ 缺乏相关的基因。
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来源期刊
CiteScore
5.80
自引率
9.50%
发文量
165
审稿时长
1 months
期刊介绍: The International Journal of Legal Medicine aims to improve the scientific resources used in the elucidation of crime and related forensic applications at a high level of evidential proof. The journal offers review articles tracing development in specific areas, with up-to-date analysis; original articles discussing significant recent research results; case reports describing interesting and exceptional examples; population data; letters to the editors; and technical notes, which appear in a section originally created for rapid publication of data in the dynamic field of DNA analysis.
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