Analysis Of Genetic Factors Of Intellectual Disability In Children Based On High Throughput Sequencing Technology

Objective:Intellectual disability(ID)is a neurodevelopmental disorder characterized by significant defects in intellectual function and adaptive behavior before the age of 18.Genetic factors are the main causes of ID.At present,when using conventional methods for genetic factors detection,more than 1/2 of ID patients still have no clear cause.High-throughput whole exome sequencing(WES)and copy number variation sequencing(CNV-Seq)were conducted for detection of single gene mutation and copy number variation on children with unexplained ID in this study.Make it clear that the cause of ID,provide genetic counseling and fertility guidance for patients,and expand the research target for the research on the pathogenesis of ID.Methods:1.Collected clinical and family data of children with unexplained ID;2.Karyotype analysis was conducted on children to exclude common chromosomal diseases related to ID;3.WES was conducted to screen the pathogenic genes of ID children with unclear etiology;4.CNV-Seq was conducted to detect micro-deletions and micro-duplications of children with negative WES results;5.Conservative analysis and three-dimensional protein structure simulation prediction of new mutation loci.Results:1.A total of 19 children with unexplained ID were enrolled.Except for 5 cases,karyotype analysis was not performed.2 of the 14 children were polymorphic(46,XX,1qh + and 46,XX,1qh +,9qh +),and the remain were not found with chromosomal abnormalities;2.After WES,9 of 19 children were identified with ID-related gene mutations: NIPBL,ASXL3,FGFR3,COL4A1,TBR1,KMT2 D,CHD7,ATP7 B,TUBA1A,2 children with gene mutations that related to other phenotypes,and 2 children with VUS gene mutations;3.After CNV-Seq,3 out of 10 children with WES negative results were identified with pathogenic CNVs;4.After karyotype analysis and WES accompanied by CNV-Seq,a total of 12 patients were diagnosed with a diagnosis rate of 63.2%;5.The mutation loci of COL4A1,TBR1,KMT2 D,CHD7 and TUBA1 A gene are highly conserved among different species.The single-base mutation of CHD7 gene has no effect on the spatial conformation of the protein,but will change the internal structure of the protein;TBR1 and TUBA1 A genes with frameshift mutations result in truncated and extended proteins,respectively,which may affect protein function.Conclusions:1.WES accompanied by CNV-Seq can improve the diagnosis rate of ID,which is an effective strategy for unexplained ID gene detection at present;2.Identified novel mutation loci related to ID of COL4A1,TBR1,KMT2 D,CHD7,TUBA1 A genes in this study;3.Further confirmed that ID has extreme genetic heterogeneity in this study.