RYR2基因变异导致儿茶酚胺敏感性多形性室性心动过速5例患儿的临床表型及遗传学分析

Clinical and genetic analysis of five children with Catecholaminergic polymorphic ventricular tachycardia due to variants of RYR2 gene

目的探讨5例儿茶酚胺敏感性多形性室性心动过速(CPVT)患儿的临床特点及遗传学特征。方法选取在2019年11月至2021年11月河南省儿童医院心内科收治的临床表现符合CPVT的5例患儿作为研究对象,收集患儿的临床资料。对所有患儿进行家系全外显子组测序,应用Sanger测序验证候选变异。应用β受体抑制剂普萘洛尔对患儿进行治疗并追踪随访。结果5例患儿均以晕厥为首发表现,均在运动状态下发病,心电图检测均显示窦性心动过缓。5例患儿首次发病年龄为(10.4±2.19)岁,延误诊断时间为(1.6±2.19)年。5例患儿RYR2基因变异位点均为新发变异,分别为c.6916G>A(p.V2306I)、c.527G>C(p.R176P)、c.12271G>A(p.A4091T)、c.506G>T(p.R169L)和c.6817G>A(p.G2273R),变异类型均为错义变异。依据美国医学遗传学与基因组学学会变异评级指南,c.527G>C(p.R176P)变异评级为致病性变异(PS2+PM1+PM2Supporting+PM5+PP3+PP4),c.6817G>A(p.G2273R)变异评级为可能致病性变异(PS2+PM2Supporting+PP3+PP4)。予以5例患儿普萘洛尔治疗,症状明显好转,并随访至2022年7月30日均未再出现晕厥。结论c.527G>C(p.R176P)、c.6817G>A(p.G2273R)的发现拓展了RYR2基因变异谱。对CPVT患者进行基因检测可以明确其致病原因,为其临床诊断提供依据,并为遗传咨询提供参考。

Objective To explore the clinical and genetic characteristics of five children with Catecholaminergic polymorphic ventricular tachycardia(CPVT).Methods Five children with clinical manifestations consistent with CPVT admitted to the Department of Cardiology of Children′s Hospital Affiliated to Zhengzhou University from November 2019 to November 2021 were selected as the study subjects.Their clinical data were collected.Potential variants were detected by whole exome sequencing,and Sanger sequencing was used to verify the candidate variants.All patients were treated withβ-blocker propranolol and followed up.Results All patients had developed the disease during exercise and presented with syncope as the initial clinical manifestation.Electrocardiogram showed sinus bradycardia.The first onset age of the 5 patients were(10.4±2.19)years,and the time of delayed diagnosis was(1.6±2.19)years.All of the children were found to harbor de novo heterozygous missense variants of the RYR2 gene,including c.6916G>A(p.V2306I),c.527G>C(p.R176P),c.12271G>A(p.A4091T),c.506G>T(p.R169L)and c.6817G>A(p.G2273R).Among these,c.527G>C(p.R176P)and c.6817G>A(p.G2273R)were unreported previously.Based on the guidelines from the American College of Medical Genetics and Genomics(ACMG),the c.527G>C(p.R176P)was classified as a pathogenic variant(PS2+PM1+PM2_Supporting+PM5+PP3+PP4),and the c.6817G>A(p.G2273R)was classified as a likely pathogenic variant(PS2+PM2_Supporting+PP3+PP4).The symptoms of all children were significantly improved with the propranolol treatment.And none has developed syncope during the follow up.Conclusion Discovery of the c.527G>C(p.R176P)and c.6817G>A(p.G2273R)variants has expanded the mutational spectrum of theRYR2 gene.Genetic testing of CPVT patients can clarify the cause of the disease and provide a reference for their genetic counseling.