Rare Genetic Variants in Young Adults Requiring Pacemaker Implantation

IF 8 1区 医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS JACC. Clinical electrophysiology Pub Date : 2024-10-01 DOI:10.1016/j.jacep.2024.05.008
{"title":"Rare Genetic Variants in Young Adults Requiring Pacemaker Implantation","authors":"","doi":"10.1016/j.jacep.2024.05.008","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Genetic disease has recently emerged as a cause of cardiac conduction disorders (CCDs), but the diagnostic yield of genetic testing and the contribution of the different genes to CCD is still unsettled.</div></div><div><h3>Objectives</h3><div>This study sought to determine the diagnostic yield of genetic testing in young adults with CCD of unknown etiology requiring pacemaker implantation. We also studied the prevalence of rare protein-altering variants across individual genes and functional gene groups.</div></div><div><h3>Methods</h3><div>We performed whole exome sequencing in 150 patients with CCD of unknown etiology who had permanent pacemaker implanted at age ≤60 years at 14 Spanish hospitals. Prevalence of rare protein-altering variants in patients with CCD was compared with a reference population of 115,522 individuals from gnomAD database (control subjects).</div></div><div><h3>Results</h3><div>Among 39 prioritized genes, patients with CCD had more rare protein-altering variants than control subjects (OR: 2.39; 95% CI: 1.75-3.33). Significant enrichment of rare variants in patients with CCD was observed in all functional gene groups except in the desmosomal genes group. Rare variants in the nuclear envelope genes group exhibited the strongest association with CCD (OR: 6.77; 95% CI: 3.71-13.87). Of note, rare variants in sarcomeric genes were also enriched (OR: 1.73; 95% CI: 1.05-3.10). An actionable genetic variant was detected in 21 patients (14%), with <em>LMNA</em> being the most frequently involved gene (4.6%).</div></div><div><h3>Conclusions</h3><div>Unrecognized rare genetic variants increase the risk of CCD in young adults with CCD of unknown etiology. Genetic testing should be performed in patients age ≤60 years with CCD of unknown etiology. The role of genetic variants in sarcomeric genes as a cause of CCD should be further investigated.</div></div>","PeriodicalId":14573,"journal":{"name":"JACC. Clinical electrophysiology","volume":null,"pages":null},"PeriodicalIF":8.0000,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"JACC. Clinical electrophysiology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S2405500X24003670","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CARDIAC & CARDIOVASCULAR SYSTEMS","Score":null,"Total":0}
引用次数: 0

Abstract

Background

Genetic disease has recently emerged as a cause of cardiac conduction disorders (CCDs), but the diagnostic yield of genetic testing and the contribution of the different genes to CCD is still unsettled.

Objectives

This study sought to determine the diagnostic yield of genetic testing in young adults with CCD of unknown etiology requiring pacemaker implantation. We also studied the prevalence of rare protein-altering variants across individual genes and functional gene groups.

Methods

We performed whole exome sequencing in 150 patients with CCD of unknown etiology who had permanent pacemaker implanted at age ≤60 years at 14 Spanish hospitals. Prevalence of rare protein-altering variants in patients with CCD was compared with a reference population of 115,522 individuals from gnomAD database (control subjects).

Results

Among 39 prioritized genes, patients with CCD had more rare protein-altering variants than control subjects (OR: 2.39; 95% CI: 1.75-3.33). Significant enrichment of rare variants in patients with CCD was observed in all functional gene groups except in the desmosomal genes group. Rare variants in the nuclear envelope genes group exhibited the strongest association with CCD (OR: 6.77; 95% CI: 3.71-13.87). Of note, rare variants in sarcomeric genes were also enriched (OR: 1.73; 95% CI: 1.05-3.10). An actionable genetic variant was detected in 21 patients (14%), with LMNA being the most frequently involved gene (4.6%).

Conclusions

Unrecognized rare genetic variants increase the risk of CCD in young adults with CCD of unknown etiology. Genetic testing should be performed in patients age ≤60 years with CCD of unknown etiology. The role of genetic variants in sarcomeric genes as a cause of CCD should be further investigated.
查看原文
分享 分享
微信好友 朋友圈 QQ好友 复制链接
本刊更多论文
需要植入起搏器的年轻成年人中的罕见基因变异。
背景:近来,遗传病已成为心脏传导障碍(CCD)的病因之一,但基因检测的诊断率以及不同基因对CCD的影响仍未确定:本研究旨在确定需要植入起搏器的病因不明的 CCD 年轻成人的基因检测诊断率。我们还研究了单个基因和功能基因组中罕见的改变蛋白质的变体的发生率:我们对 150 名病因不明的 CCD 患者进行了全外显子组测序,这些患者在年龄小于 60 岁时在西班牙 14 家医院植入了永久性心脏起搏器。我们将 CCD 患者中罕见的蛋白质改变变体的发生率与 gnomAD 数据库中的 115,522 个参照人群(对照组)进行了比较:在 39 个优先基因中,CCD 患者的罕见蛋白质改变变异多于对照受试者(OR:2.39;95% CI:1.75-3.33)。除脱膜体基因组外,在所有功能基因组中都观察到了CCD患者罕见变异的显著富集。核包膜基因组中的罕见变异与CCD的关联性最强(OR:6.77;95% CI:3.71-13.87)。值得注意的是,肉瘤基因中的罕见变异也有富集(OR:1.73;95% CI:1.05-3.10)。21名患者(14%)检测到了可操作的基因变异,其中LMNA是最常涉及的基因(4.6%):结论:未被发现的罕见基因变异会增加病因不明的年轻成人罹患 CCD 的风险。对于年龄小于60岁、病因不明的CCD患者,应进行基因检测。应进一步研究肉瘤基因中的遗传变异在 CCD 病因中的作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
求助全文
约1分钟内获得全文 去求助
来源期刊
JACC. Clinical electrophysiology
JACC. Clinical electrophysiology CARDIAC & CARDIOVASCULAR SYSTEMS-
CiteScore
10.30
自引率
5.70%
发文量
250
期刊介绍: JACC: Clinical Electrophysiology is one of a family of specialist journals launched by the renowned Journal of the American College of Cardiology (JACC). It encompasses all aspects of the epidemiology, pathogenesis, diagnosis and treatment of cardiac arrhythmias. Submissions of original research and state-of-the-art reviews from cardiology, cardiovascular surgery, neurology, outcomes research, and related fields are encouraged. Experimental and preclinical work that directly relates to diagnostic or therapeutic interventions are also encouraged. In general, case reports will not be considered for publication.
期刊最新文献
Left Ventricular Summit Arrhythmias: State-of-the-Art Review of Anatomy, Mapping, and Ablation Strategies. Predictors of Clinical Success of Cardioneuroablation in Patients With Syncope: Results of a Multicenter Study. Long-Term Differences in Autonomic Alterations After Cryoballoon vs Radiofrequency Atrial Fibrillation Ablation. Shorter Premature Atrial Complex Coupling Interval Leads to Mechanical Dysfunction, Fibrosis, and AF in Swine. Visualization of Mechanisms for Myocardium-Originating Premature Ventricular Contractions With Narrow QRS Via His-Purkinje System.
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
×
提示
您的信息不完整,为了账户安全,请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
已复制链接
已复制链接
快去分享给好友吧!
我知道了
×
扫码分享
扫码分享
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号:481959085
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们:info@booksci.cn
Book学术提供免费学术资源搜索服务,方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1