TRDN基因变异所致Triadin敲除综合征1例的临床及遗传学分析并文献复习

Clinical and genetic analysis of a case of Triadin knockout syndrome due to variant of TRDN gene and a literature review

目的探讨1例Triadin敲除综合征(TKOS)儿童的遗传学病因与临床表型,并对TRDN基因变异所致TKOS患者相关文献进行复习。方法选择2023年3月19日,因3 d前突发心脏骤停,送至山西省运城市稷山正身医院抢救治疗效果不佳,转诊至西安交通大学附属儿童医院治疗的1例TKOS患儿作为研究对象。采集本研究患儿及其父母外周血样2~3 mL,提取患儿基因组DNA并进行全外显子组测序(WES)。检索美国基因组聚合数据库(gnomAD)、美国在线人类孟德尔数据库(OMIM)等,对患儿致病基因变异进行筛查,根据美国医学遗传学与基因组学学会(ACMG)制定的《遗传变异分类标准与指南》,对患儿基因变异位点进行致病性评级,并采用Sanger测序法,对患儿致病基因变异进行家系验证。分别以"心律失常""arrhythmias""TRDN"和"Triadin"为中、英文关键词,在中国知网数据库、万方数据知识服务平台和美国PubMed数据中,检索TRDN基因变异所致TKOS患者相关文献,检索时限设定为2012年1月1日至2023年12月1日。对检索文献进行复习,并绘制TKOS患者TRDN基因变异图谱。本研究遵循的研究程序通过了西安交通大学附属儿童医院医学伦理委员会的审查(审批文号:20230097),并与患儿监护人签署临床研究知情同意书。结果本研究患儿运动后发生晕厥和心脏骤停,其心电图检查结果显示,QTc间期延长,胸前V1~V3导联T波倒置,心率增快时出现多形性室性早搏(VPB)及室性心动过速(VT)。WES和Sanger测序检测结果显示,该患儿TRDN基因发生c.463del(p.E155Kfs*20)纯合变异,其父母均为该基因杂合变异携带者。根据ACMG制定的《遗传变异分类标准与指南》,该基因变异被判断为致病性变异(PVS1+PM2_Supporting+PM3)。根据患儿临床表现与基因检测结果诊断为TKOS患儿。根据本研究设定的文献检索策略,共检索到12篇TRDN基因变异所致TKOS病例报道,涉及30例TKOS患者及28例TRDN基因单个杂合变异携带者。30例TOKS患者中,20例为TRDN基因纯合变异携带者与10例为复合杂合变异携带者,均具有显著心律失常等临床表型,多于婴幼儿期或儿童早期出现运动或情绪激动诱发的恶性心律失常,并导致反复晕厥或心脏骤停。28例TRDN基因单个杂合变异携带者临床表型均未见异常。结论本研究首次报道了TRDN基因c.463del(p.E155Kfs*20)纯合变异,丰富了TRDN基因变异谱。该变异可能为TKOS患儿心脏骤停的遗传学病因。

Objective To explore the genetic etiology and clinical phenotype of a child with Triadin knockout syndrome(TKOS),and to review the relevant literature of TKOS patients due to variants of TRDN gene.Methods A child who was admitted to the Children′s Hospital of Xi′an Jiaotong University on March 19,2023 due to sudden cardiac arrest 3 days earlier was selected as the study subject.Peripheral blood samples(2 to 3 mL)were collected from the child and her parents for the extraction of genomic DNA and whole exome sequencing(WES).Pathogenic variants were searched from databases such as the Genome Aggregation Database(gnomAD)and Online Mendelian Inheritance in Man(OMIM),and were assessed based on the guidelines from the American College of Medical Genetics and Genomics(ACMG).Sanger sequencing was carried out for family validation of the pathogenic variants.Using keywords such as"arrhythmias""TRDN"and"Triadin"both in Chinese and English,relevant literature on TKOS patients due to variants of the TRDN gene was retrieved from the CNKI,Wanfang Data Knowledge Service Platform,and PubMed databases,and the time of literature retrieval was set from January 1,2012 to December 1,2023.This study has been approved by the Ethics Committee of the Affiliated Children′s Hospital of Xi′an Jiaotong University(No.20230097),and informed consent was obtained from the parents of the child.Results The child had experienced syncope and cardiac arrest after exercise.Electrocardiographic examination revealed QTc interval prolongation,T-wave inversion in precordial leads V1-V3,polymorphic ventricular premature beat(VPB),and ventricular tachycardia(VT)along with increased heart rate.WES and Sanger sequencing revealed that the child has harbored a homozygous c.463del(p.E155Kfs*20)variant of the TRDN gene,for which both of the parents were heterozygous.Based on the guidelines from the ACMG,the variant was classified as pathogenic(PVS1+PM2+PM3).The child was ultimately diagnosed with TKOS.In total 12 publications on TOKS cases caused by TRDN gene variants were retrieved,which involved 30 patients and 28 carriers of single heterozygous variant of the TRDN gene.Among the 30 TKOS patients,20 had carried homozygous variants of the TRDN gene,and 10 had carried compound heterozygous variants,and all had exhibited significant clinical phenotype of arrhythmia,with most cases had experienced malignant arrhythmia induced by exercise and/or excitement during infancy or early childhood,leading to recurrent syncope and cardiac arrest.Of note,none of the 28 carriers of single heterozygous variant had abnormal clinical phenotype.Conclusion The homozygous c.463del(p.E155Kfs20)variant of the TRDN gene probably underlay the pathogenesis of cardiac arrest in this child.Above discovery has enriched the mutational spectrum of the TRDN gene.This mutation may represent a genetic cause for cardiac arrest in children with TKOS.