南京医科大学学报（自然科学版）2025，Vol.45Issue(6)：816-825,10.DOI:10.7655/NYDXBNSN241492
基于全外显子组测序的1 096例智力障碍或全面性发育迟缓患儿遗传学病因构成分析
Genetic etiology analysis of 1 096 patients with intellectual disability or global developmental delay based on whole exome sequencing
摘要
Abstract
Objective:To investigate the molecular diagnostic value of whole exome sequencing(WES)in the genetic etiology of intellectual disability(ID)or global developmental delay(GDD)and to analyze of genetic characteristics in the Chinese cohort.Methods:Patients with ID/GDD who were enrolled in Children's Hospital of Nanjing Medical University from January 2019 to December 2021 were selected as the study objects.Inclusion criteria adhered to clinical guidelines for significant developmental milestone delays,with exclusion of non-genetic factors(e.g.,perinatal hypoxia,infection,metabolic abnormalities).We retrospectively analyzed sequence variants and copy number variations(CNVs)detected by Trio-whole exome sequencing(Trio-WES)or proband-only WES,classifying variants according to the American College of Medical Genetics and Genomics(ACMG)guidelines,with pathogenic(P)/likely pathogenic(LP)variants defined as positive results.Results:1 096 patients with ID/GDD ranged in age from 1 month to 15 years,with a median age of 24(12,48)months,including 716 males and 380 females.The overall positive diagnostic rate was 35.31％(387/1 096),with monogenic variants identified in 271 patients and CNVs in 116 patients.Among the monogenic variants,MECP2 gene was the most common one(12/271,4.43％),primarily associated with Rett syndrome,followed by SYNGAP1 and DDX3X.For CNVs,5.17％(6/116)patients were aneuploidies,with 7q11.23 deletions(associated with Williams syndrome)being the most common(8.62％,10/116).Autosomal dominant inheritance accounted for 71.96％(195/271)of monogenic variants,while X-linked inheritance represented 19.93％(54/271).Sanger sequencing confirmed de novo origins in 68.27％(185/271)of detected variants.Clinical phenotypic analysis demonstrated a significantly higher positive rate in isolated ID/GDD cases compared to those with comorbid autism spectrum disorder(ASD)or attention-deficit/hyperactivity disorder(ADHD)(P<0.05).Conclusion:The combined analysis of WES and CNV significantly enhances the molecular diagnostic yield for ID/GDD.High frequencies of MECP2 variants and 7q11.23 deletions represent high-frequency findings in the Chinese pediatric cohort.De novo variants constitute the primary genetic etiology in this cohort.These findings support the implementation of WES as a first-line clinical diagnostic tool for ID/GDD.关键词
智力障碍/全面性发育迟缓/全外显子组测序Key words
intellectual disability/global developmental delay/whole exome sequencing分类
临床医学引用本文复制引用
傅绿函,施玮,张胜男,王春莉,郑必霞,贾占军,周玮,张爱华..基于全外显子组测序的1 096例智力障碍或全面性发育迟缓患儿遗传学病因构成分析[J].南京医科大学学报（自然科学版）,2025,45(6):816-825,10.基金项目
江苏重点研发计划社会发展项目(BE2023663) （BE2023663）
