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

doi:10.11852/zgetbjzz2022-1361

中国儿童保健杂志 ›› 2023, Vol. 31 ›› Issue (8): 889-894.DOI: 10.11852/zgetbjzz2022-1361

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

冯金彩¹, 赵婷婷², 贾佳³, 田园⁴, 邵达⁵, 于广军³

1.上海交通大学医学院附属儿童医院,上海市儿童医院康复科,上海 200333;
2.上海交通大学医学院附属儿童医院,上海市儿童医院生物医学信息研究中心,上海 200333;
3.上海交通大学医学院附属儿童医院,上海市儿童医院儿童精准医学大数据工程技术研究中心,上海 200333;
4.上海交通大学医学院附属儿童医院,上海市儿童医院儿保科,上海 200333;
5.上海交通大学医学院附属儿童医院,上海市儿童医院科研处,上海 200333

收稿日期:2022-11-11 修回日期:2023-03-13 发布日期:2023-08-18
通讯作者: 于广军,E-mail: gjyu@shchildren.com.cn
作者简介:冯金彩(1975-),女,湖北人,副主任医师,硕士学位,主要研究方向为儿童康复。
基金资助:
上海申康医院发展中心临床三年行动计划(SHDC2020CR1047B,SHDC2020CR6028);上海交通大学“转化医学国家重大科技基础设施(上海)开放课题项目”(TMSK-2021-142)

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

FENG Jincai¹, ZHAO Tingting², JIA Jia², TIAN Yuan³, SHAO Da⁴, YU Guangjun⁵

1. Department of Rehabilitation, Shanghai 200333, China;
2. Center for Biomedical Informatics, Shanghai 200333, China;
3. Shanghai Engineering Research Center for Big Data in PediatricPrecision Medicine,, Shanghai 200333, China;
4. Department of Children Healthcare, Shanghai 200333, China;
5. Department of Science and Research,Shanghai Children's Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200333, China

Received:2022-11-11 Revised:2023-03-13 Published:2023-08-18
Contact: YU Guangjun,E-mail: gjyu@shchildren.com.cn

摘要/Abstract

摘要： 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。

关键词: 发育迟缓/智力障碍, 核心家系全外显子组检测, 遗传检测, 基因变异

Abstract: 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-Ⅳ or WISC-Ⅳ as 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.

Key words: developmental delay/intellectual disability, Trios-Whole-Exome Sequencing, genetic testing, genetic variation

中图分类号:

R749.94

冯金彩, 赵婷婷, 贾佳, 田园, 邵达, 于广军. 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[J]. 中国儿童保健杂志, 2023, 31(8): 889-894.

FENG Jincai, ZHAO Tingting, JIA Jia, TIAN Yuan, SHAO Da, YU Guangjun. Genetic characteristics of 58 children with unexplained developmental delay/intellectual disability analyzed by Trios-WES[J]. Chinese Journal of Child Health Care, 2023, 31(8): 889-894.

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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

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