一个猝死家系的遗传基因检测与临床表型分析

Phenotypic Analysis Combined with Genetic Testing to Determining The Cause of Sudden Death Onset as The First Symptom in A Pedigree

目的对一个猝死家系行遗传基因检测和临床表型分析,明确该家系猝死的病因,探索以猝死为首发症状病因诊断的合理方法。对象和方法收集猝死家系成员的资料,包括临床资料和静脉血,进行临床表型分析。利用高通量二代测序技术,对于目前报道的心源性猝死相关基因进行基因检测,发现基因变异后行Sanger法测序验证。1300例健康者作为对照。根据已有的研究结果和软件分析,对发现的遗传变异进行致病性分析。结果表型分析提示本猝死家系为心源性猝死,分析可疑患者(两次不明原因的晕厥、其父为猝死先证者)的临床资料,除心电图发现窦性心动过缓、ST-T改变和间歇性QT间期延长(QT/QTc 536 ms/494 ms)外,未发现其他临床线索,综合分析临床资料,最可能的致病原因为长QT综合征(LQTs)。可疑患者遗传基因检测发现3个罕见基因变异CACNA1C c.G2573A,R858H、SCN1B基因c.C566T,p.T189M、SYNE2 c.C585A,p.C195X。其子也携带同样的三个罕见基因变异。其中CACNA1C R858H突变为肯定致病突变,能够导致LQTs 8型。虽然其子无明显临床症状,但也具有明确猝死风险。结论 LQTs 8型是导致该家系猝死的最可能病因,CACNA1C R858H突变是其遗传病因。临床表型分析结合遗传基因检测,能够指导临床更加精准的识别猝死病因,基因检测对于家系成员的早期诊断价值大。

Objective To develop a reasonable method for determining the cause of sudden death onset as the first symptom in a pedigree. Methods Data on members of the sudden death pedigree including clinical information and venous blood were collected and analyzed. One hundred and six genes associated with sudden cardiac death reported were detected using high-throughput secondgeneration sequencing technology. Genetic variations identified should be verified using Sanger sequencing. One thousand and three hundred healthy subjects served as controls. Results Phenotypic analysis of the suspected patient with unexplained syncope,whose father as a proband died of suddenly, suggested that the most likely reason of sudden death of the family members was long QT syndrome（LQTs）.Three rare gene mutations were identified in the patient and his son. The pathogenic mutations was CACNA1 C c.G2573 A, R858 H according the reported results and the characteristics of the patient. Conclusion LQTs was the most likely cause of sudden death in this family, and the CACNA1 C R858 H mutation was the genetic cause. Phenotypic analysis combined with genetic testing which was of great value in the early diagnosis of family members could guide the clinic to identify the cause of sudden death more accurately.