利用Trios-WES检测分析58例不明原因发育迟缓/智力障碍儿童的遗传学特征

Genetic characteristics of 58 children with unexplained developmental delay/intellectual disability analyzed by Trios-WES

目的采用基于全外显子组测序的单核苷酸变异(SNV)/小插入缺失(InDel)和拷贝数变异(CNV)家系分析(Trios-WES)提高发育迟缓/智力障碍(DD/ID)诊断能力。方法纳入2017年3月1日—2019年3月31日期间,就诊于上海市儿童医院高危儿整合门诊及康复科门诊,经Gesell、WPPSI-Ⅳ或WISC-Ⅳ评估非外在因素引起、常规遗传检测为阴性、原因不明的58例DD/ID患儿,采用Trios-WES技术分析,对所发现基因变异进一步进行表型与Sanger测序验证,统计与分析结果。结果58例原因不明的DD/ID患儿,经Trios-WES分析,发现41个DD/ID相关的基因变异,其中13个首次报道。33个基因变异(33/58,56.9%)经验证为致病性单基因或多基因变异,包括3例CNV变异和1例父源单亲二倍体;含10个错义突变,7个剪切突变,7个移码突变,5个无义突变;新发变异占所有致病变异的79%;其中MECP2、TCF4、SYNGAP1、UBE3A、SHANK3基因变异高频出现。结论采用Trios-WES临床遗传检测策略,可提高不明原因DD/ID患儿的诊断率,为其进一步治疗及遗传咨询提供依据。

Objective To improve diagnostic accuracy of developmental delay/intellectual disability(DD/ID)using genetic variation analysis of single nucleotide variant(SNV)/small insertion-deletion(InDel)and copy number variant(CNV)based on Trios-whole-exome sequencing(Trios-WES).Methods From March 1st,2017 to March 31st,2019,58 children with DD/ID were enrolled and analyzed by Trios-WES technique,who were treated in the High-Risk Infants Multi-Disciplinary Treatment Outpatient and Rehabilitation Department Outpatient of Shanghai Children's Hospital,and were assessed by Gesell,WPPIS-Ⅳor WISC-Ⅳas non-external factors,negative by conventional genetic tests,and with unexplained reasons.Further phenotypic confirmation and Sanger sequencing verification were performed to analyze the results.Results Among 58 unknown-cause children with DD/ID,41 DD/ID related gene variants were identified by Trios-WES analysis and 13 genes variants were reported for the first time.Thirty-threegenes variants(33/58,56.9%)were found to be pathogenic single genes or multiple gene variants,including three CNV variants and one paternal uniparental disomy(UPD).There were 10 missense variants,7 splicing variants,7 frameshift variants and 5 nonsense variants.The de novo variants accounted for 79%of all pathogenic variants.Among them,MECP2,TCF4,SYNGAP1,UBE3A and SHANK3 gene variants appeared frequently.Conclusions The clinical genetic testing strategy of Trios-WES analysis can improve the diagnosis rate of children with unexplained DD/ID,help to identify the cause,and provide a basis for further treatment and genetic counseling.