Analysis Of Genome-wide Copy Number Variations In 150 Children With Intellectual Disability/Developmental Delay

Background:Intellectual disability(ID)is defined as severe impairment of cognitive and adaptive function before 18 years old,and Developmental delay(DD)is usually used to describe children before 5 years old.The intelligence quotient(IQ)of children with ID is lower than the mean of the population by two standard deviations or less than 70.Children under 5 year old cannot rely on IQ to diagnose DD.DD is defined as a significant delay in two or more aspects:adaptation,gross motor,fine motor,language,social.According to foreign studies,ID/DD affect 1-3%of the population.The prevalence rate of ID/DD in China is about 1.2%,genetic diseases account for 40.5%of all factors before birth and account for 17.7%of all known causes of ID/DD.The cause is still unclear in more than one-fifth children with ID/DD.In recent years,the application of chromosomal microarray analysis technology in genome-wide copy number variations has provided a powerful tool for the search for genetic causes of children with ID/DD.Compared with the 3-5%detection rate of traditional karyotype analysis,CMA can identify the genetic cause for 20%of ID/DD children,and has become a first-line detection method for unidentified ID/DD.Because of the high disability rate of ID/DD and the lack of specific treatment,it brings heavy economic and psychological burden to patients and families.The most effective treatment for ID/DD patients is rehabilitation training.Some studies have shown that as the age of ID/DD children grows,the effectiveness of rehabilitation treatment gradually decreases,so early CMA detection of children with ID/DD is of great importance for early diagnosis,intervention and eugenics in the later period.Objective:Chromosomal microarray analysis was used to detect the genome-wide copy number variation of 150 Chinese children with Intellectual disability/Developmental Delay(ID/DD),and to explore the clinical application value of CMA in the diagnosis of genetic etiology of DD/ID children.Common CNVs of Han Chinese children were found and analyzed their pathogenicity.Source analysis was carried out on some CNVs to provide a theoretical basis for reproduction and genetic counseling.Methods:150 children diagnosed as DD/ID in Qilu Children’s Hospital of Shandong University from June 2015 to October 2017 were taken as the study object.The genomic DNA was extracted and the copy number variation of the child’s genome was detected.The detected copy number variation was analyzed using OMIM,decipher,PubMed,UCSC,ISCA,ClinGen and other databases to determine its pathogenicity.Source analysis of CNVs was performed on children whose parents’blood samples were available.Results:1.61 chromosome abnormal fragments were found in 50 patients.There was one chromosome deletion fragment in 26 children;one chromosome duplication fragment in 12 children;one chromosome deletion and one chromosome duplication fragment in 7 children;two chromosome duplication fragments in 2 children and uniparental disomy in 3 children,involving five chromosomal abnormalities.2.Among the 150 ID/DD children,a total of 46 children were found to have pathogenic chromosomal abnormalities(30.7%).Among them,2 cases had large segment homozygote,which was considered to be related to uniparental disomy,and 44 cases had pathogenic CNVs.CMA also detected 1 child with likely pathogenic CNVs,3 children with CNVs of unknown clinical significance,and 1 child with uniparental disomy of unknown clinical siginificance.3.The diseases most commonly involved in the pathogenic chromosomal abnormalities in this study were PWS/AS,WBS，1p36 deletion syndrome,2q37 microdeletion syndrome,22q11.2 deletion syndrome,MECP2 microduplication syndrome and 9p trisomy4.In this study,qPCR was used to analyze the source of chromosomal structural abnormalities in 41 children.Three children’s chromosomal abnormalities were inherited from their father,three from their mother,and the rest were all de novo,which provided a theoretical basis for genetic counselingConclusions:1.In this study,we used CMA technology to identify the genetic cause for 30.7%of children with DD/ID,which is helpful for early intervention treatment of the children.In addition,we analyzed the origin of chromosome structural abnormalities in some children to provide the theoretical basis for later genetic counseling,so as to achieve the goal of eugenics.2.In this study,The common causes of Han Chinese children with ID/DD determined by CMA are PWS/AS,WBS,1p36 deletion syndrome,2q37 microdeletion syndrome,22q11.2 deletion syndrome,MECP2 microduplication syndrome and 9p trisomy.This provides a data base for the study of the specific detection chip of DD/ID in Han Chinese children.3.This study details the clinical manifestations of 3 children with uncertain clinical significance CNVs,providing a basis for the classification of such CNVs in the future.