CASQ2基因变异致儿童儿茶酚胺敏感性多形性室性心动过速的临床及遗传学特点分析

Clinical and genetic characteristics of catecholaminergic polymorphic ventricular tachycardia in children with CASQ2 variants

目的总结CASQ2基因变异致儿童儿茶酚胺敏感性多形性室性心动过速(CPVT)的临床特征及遗传学特点。方法回顾性分析2017年1月至2018年11月在首都医科大学附属北京儿童医院诊治的8例(男女各4例)CASQ2基因变异阳性CPVT患儿的临床资料,基因检测采用靶向高通量二代测序法,并通过Sanger进行家系成员验证。结果8例患儿平均发病年龄为6.4岁,平均确诊年龄为9.4岁,平均诊断周期为3年;仅2例首次发病即确诊,余6例均存在延迟诊断,其中3例误诊为癫痫。8例患儿均存在运动或情绪激动后出现晕厥,持续几分钟可自行恢复意识,无猝死病史及家族史。发作间期静息心电图6例未见异常,2例有轻度窦性心动过缓。动态心电图及平板运动试验记录到典型的双向性和/或多形性室性心动过速的病例数分别为8/8例、5/5例。患儿均存在CASQ2基因变异,6例为复合杂合变异,2例为纯合变异。8例患儿共检测到9个CASQ2基因变异位点,其中5个为未报道的新变异。经家系验证,8例患儿均为家族遗传性变异,无新发变异。8例患儿均予β受体阻滞剂口服治疗,无症状反复发作。平均随访1.5年,1例患儿因严重窦性心动过缓植入心脏复律除颤器,无死亡病例。结论CASQ2基因变异所致儿童CPVT,绝大多数在学龄前期起病,表现为运动或情绪激动后反复晕厥,双向性和/或多形性室性心动过速为其突出特点。延迟诊断和误诊较普遍,β受体阻滞剂治疗具有较好有效性和安全性。5个新变异丰富了CASQ2的基因突变谱。

Objective To summarize the clinical and genetic characteristics of catecholaminergic polymorphic ventricular tachycardia(CPVT)in children caused by CASQ2 gene variants.Methods The clinical data of 8 children(4 males and females,respectively)with CPVT caused by CASQ2 gene variants admitted to Beijing Children′s Hospital,Capital Medical University from January 2017 to November 2018 were retrospectively analyzed.The targeted next generation sequencing was employed to identify CASQ2 variants and Sanger sequencing was conducted to conform the candidate variants and determine the parental origin.Results As for 8 children in this study,the average age of onset was 6.4 years,the mean age at diagnosis was 9.4 years,and the average interval from onset to diagnosis was 3 years.Only 2 cases had clearly diagnosis at onset,other 6 cases had a delay to diagnosis and 3 cases of them were diagnosed at other hospitals as having epilepsy and did not respond to anti-epileptic therapy.During physical activity and/or emotional stress,8 cases presented with recurrent syncope and were able to regain consciousness after a few minutes.They had no a history of sudden cardiac death or family history.There was no abnormality on resting electrocardiogram during the paroxysmal interval in 6 cases and mild sinus bradycardia in 2 cases.Typical bidirectional ventricular tachycardia(VT)and/or polymorphic VT were detected in 8/8 cases and 5/5 cases,respectively,based on Holter electrocardiography and cardiac stress test.The CASQ2 gene variant was found in all children,with 6 cases carrying compound heterozygous variants and 2 cases carrying homozygous variants.A total of 9 different CASQ2 variants were detected in 8 cases,of which 5 had not been previously reported.According to the family-line verification,all of them had a familial variant,with no novel variants.All 8 cases were treated orally withβ-blockers,with asymptomatically recurrent episodes,with a mean follow-up of 1.5 years,during which implantable cardioverter defibrillation was performed in 1 case owing to severe sinus bradycardia.There was no death case among them.Conclusions CPVT with CASQ2 variants is characterized by early onset before preschool age,recurrent syncope after exercise or emotional stress and bidirectional/polymorphic VT.Early diagnosis of CPVT remains challenging due to delayed diagnosis or misdiagnosis.Treatment withβ-blockers can achieve favorable effectiveness and safety.Five novel variants in this study would further expand the database of CASQ2 genes.