Application Of WES Combined With HPO In Diagnosis Of Neurodevelopmental Disorders

Neurodevelopmental disorders(NDDs)affect about 2?5%of children,and their clinical phenotypes are mainly intellectual disability,attention deficit hyperactivity disorder(ADHD),autism spectrum disorder(ASD),communication disorder,motor disorders,specific learning disorder.Differential diagnosis of the causes of NDDs is relatively time consuming and expensive,and there is usually no definitive diagnosis.Traditional methods include karyotype,copy number variation(CNV),etc.,and the diagnostic rate of NDDs patients is less than 30%.Previous studies have reported significant clinical and genetic heterogeneity in NDDs patients,leading to difficulties in identification of etiology.Although the next-generation sequencing technology(whole exome sequencing and whole genome sequencing)has used to diagnose patients with NDDs,but its clinical and cost-effectiveness are unclear although clinical fully sequenced exons group is increasingly used in rare Mendelian disease diagnosis,but in establishing a genotype-phenotype correlation disease genes or mutations,in order to solve the calculation analysis aspect still a gap.HPO for further phenotypic analysis provides the most comprehensive bioinformatics resources,is the bridge of genome biology to clinical medicine,which is gradually used in analysis and differential diagnosis of rare disease phenotype.Exomiser biological phenotype data using clinical data model and random walk analysis of protein interaction data to perform the prioritization.OBJECTIVEThis study intends to use standardized patients HPO phenotypic information,data and combined with fully sequenced exons exomiser application priorities for candidates variation,in order to identify potential virulence genes and mutations or to the differential diagnosis of Mendelian genetic disorders,helps to identify genetic disease causes,to describe the genotype-phenotype of related to provide more accurate information,in order to determine the appropriate treatment measures and provide basis for the clinical management strategies.METHODS45 trio or quad core families of NDDs that could not be diagnosed by traditional diagnostic methods were recruited.The clinical phenotype of each core family was obtained by examining the medical history and physical examination of the proband.Standardize the phenotype using Human Phenotype Ontology(HPO).Then 45 core families were subjected to WES.Sequencing data uses exomiser combined with HPO standard abnormal phenotypes to prioritize candidate variants.RESULTS(1)45 families of NDDs core families had a diagnostic rate of 49%.(2)NDDs deep phenotypic analysis revealed that the abnormal phenotype was dominated by neurological abnormalities,accompanied by multi-system abnormalities.(3)Exomiser prioritized candidate genes and screened for new mutations in multiple NDDs-related genes.(4)Using protein-protein migration analysis,four genes FOXO4,DSCAML1,TREX2 variants may be related to NDDs through protein interaction.CONCLUSIONS(1)WES combined with HPO phenotype analysis can improve the diagnostic rate(2)of NDDs children,which is of great significance for the diagnosis of genetic diseases with high phenotypic heterogeneity and low incidence rate.(3)Possible pathogenic mutations in NDDs-related genes have been reported for the first time,extending the mutant spectrum of these genes and contributing to genetic counseling and prenatal diagnosis in families.(4)Exomiser prioritizes candidate genes and uses protein-protein migration analysis to screen for new pathogenic genes.