基于全外显子组测序联合拷贝数变异的发育迟缓/智力障碍儿童遗传学病因分析

Genetic etiology analysis of developmental delay/intellectual disability in children based on whole-exome sequencing combined with copy number variation analysis

摘要

目的 分析全外显子组测序(WES)联合拷贝数变异(CNV)在不明原因发育迟缓/智力障碍(DD/ID)患儿中的诊断价值,为其在临床中应用提供科学依据。方法 选取2024年1—12月在安徽省儿童医院康复科就诊的109例不明原因的DD/ID患儿为研究对象,回顾性分析WES结果,对获得的单核苷酸变异(SNV)、小片段插入/缺失(Indel)及CNV进行系统分析,并结合家系验证和临床表型进行综合判读。结果 在SNV/Indel分析中,共发现致病性变异18个、可能致病性变异23个,阳性诊断率为37.61%。其中移码突变最常见(36.6%),合子状态以杂合为主(90.2%),主要遗传方式为常染色体显性遗传(48.8%)。CNV分析共检出12例致病性(10例)或可能致病性变异(2例),涵盖多个神经发育相关基因,额外提升诊断率11.01%。结论 WES联合CNV分析提高了不明原因DD/ID患儿的分子诊断率,为遗传咨询和精准医疗提供重要依据。

Abstract

Objective To evaluate the diagnostic value of whole-exome sequencing (WES) combined with copy number variation (CNV) analysis in children with unexplained developmental delay or intellectual disability (DD/ID), so as to provide a reference for clinical practice. Methods A retrospective study was conducted among 109 children with unexplained DD/ID who visited the Department of Rehabilitation, Anhui Provincial Children′s Hospital, from January to December 2024. WES data were analyzed to systematically evaluate single nucleotide variants (SNV), small insertions/deletions (Indel), and CNV. Pathogenicity was comprehensively interpreted integrating family validation and clinical phenotypes. Results SNV/Indel analysis identified 18 pathogenic and 23 likely pathogenic variants, with a diagnostic yield of 37.61%. Frameshift variants were the most prevalent (36.6%), and heterozygous variants constituted the majority (90.2%). Autosomal dominant inheritance was the most common mode (48.8%). Furthermore, CNV analysis identified 10 pathogenic or 2 likely pathogenic variants involving multiple genes associated with neurodevelopment, increasing the overall diagnostic yield by 11.01%. Conclusion WES combined with CNV analysis significantly improves the molecular diagnostic yield in children with unexplained DD/ID, which provides crucial reference for genetic counseling and precision medicine.

关键词

外显子测序 / 拷贝数变异 / 发育迟缓 / 智力障碍

Key words

whole-exome sequencing / copy number variation / developmental delay / intellectual disability

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基金资助

安徽省卫健委科研项目(AHWJW2022b061);安徽医科大学校科研项目(2021xkj230)