Pathogenicity Of Genetic Variants On X Chromosome For Male Children With Unknown Neurodevelopmental Disorder

ObjectiveWe estimate the enrichment of related NDD genes,LOF single nucleotide variation(SNVs)and pathogenic copy number variations(CNVs)on 23 Chromosomes.In order to improve the genetic diagnosis rate of NDD gene in male NDD cases,we selected the well-established NDD gene in X chromosome for target sequencing panel and optimize the call process for both SNVs and CNVs.We explore the pathogenic contribution of variants in X chromosome genes using a male case cohort with unknown NDD,and provide the utility evidence for the future diagnosis and genetic counseling of NDD disease.Method2070 NDD-related genes from Ingenuity Pathway Analysis(IPA),1552 genes in the DDG2 P database and 700 ID-related genes were analyzed the enrichment of NDD gene in either autosomal or X chromosome.For these NDD genes,the LOF variants of these genes were extracted from the Ex AC and Clin Var databases,and enrichment of NDD genetic variant in X chromosome was obtained by comparing the LOF variants of the two databases(Ex AC/Clin Var).We also extracted the pathogenic/liky pathogenic CNVs covering NDD genes from the Clin Gene database(Western population)and that from Chinese patient population,and repeated enrichment analysis for NDD gene in X chromosomes using different ethnic patient populations.We screened 90 known NDD genes from X chromosome,and custom designed the target sequencing panel using the Ion Torrent sequencing platform.The SNVs and CNVs of the 90 genes were detected by the optimized the call process.100 male cases with unexplained NDD were recruited and sequenced to explore the detection yield of pathogenic variants in X chromosome.Results 1.NDD-related genes were enriched in X chromosomes in three databases(IPA,DDG2 P and 700 ID genes).2.In the Clin Var and Ex AC databases,the frequency of LOF variants on X chromosomes and autosomes was statistically significant.Pathogenic CNVs covering NDD genes from the Western and Chinese patient population were also significantly enriched in X chromosome 3.After the variant call process was optimized by Ion Torrent platform targeting sequencing technology,we validated that SNV and CNV can be detected using 5 CNV-carriers and 6 SNV-carriers.4.9 pathogenic/likely pathogenic SNVs and 1 pathogenic CNV was detected from 100 unexplained male NDD cases,and the detection yield was 10%.ConclusionsNDD-related genes,their LOF mutations and pathogenic CNVs are significantly enriched on the X chromosome,which suggested that the X chromosome-related genes play an important role in the pathogenicity of NDD.The optimized high-throughput sequencing platform in this study has important diagnostic value in the diagnosis of NDD male cases.In this study,in addition pathogenic SNVs,the optimized high-throughput sequencing platform can simultaneously detect pathogenic/likely pathogenic CNVs,improving the genetic diagnosis yield.This study provided a evidence for genetic diagnosis and counseling for XLNDD disease...