Phenotypic and genetic characteristics of children with developmental delay or intellectual disability: a cohort from Northwest China

Background Intellectual disability/global developmental delay (ID/GDD) is a common neurodevelopmental disorder in childhood. In this study, the causal effects of genetic variant categories on clinical phenotypes in children with ID/GDD from Northwest China were examined under a prespecified analysis controlling all measured covariates. Methods Karyotype analysis was performed in 25 children and whole-exome sequencing (WES) in 225 of 250 children with suspected ID/GDD from Northwest China. Among the 250 children, 8 had reportable chromosomal abnormalities, 9 had reportable copy number variants (CNVs), 32 had pathogenic or likely pathogenic (P/LP) single-nucleotide variants (SNVs) and 18 had SNV-variant of uncertain significance (VUS). The genetic characteristics of these findings were analysed and their causal effects on clinical manifestations of ID/GDD were assessed. Results Loss of heterozygosity accounted for 6 of 10 CNV events (60.0%), and seven of nine CNV cases were pathogenic (77.78%). CNVs caused GDD in all nine CNV cases and Dandy-Walker syndrome in three cases. P/LP SNVs most frequently involved chromosomes 1 and X; 18 of 225 WES-tested children had SNV-VUS (8.0%). Phenotypic severity differed causally by variant category: P/LP SNVs caused abnormal muscle tone and brain MRI abnormalities, whereas karyotype abnormalities caused severe ID and delayed development of brain functional areas. Conclusions The detection of CNVs, SNVs and chromosomal karyotype abnormalities supported a close association between genotype, phenotype and clinical manifestations of children with ID/GDD in Northwest China. The combined application of karyotype analysis, chromosomal microarray analysis and WES can help improve molecular diagnostic accuracy and refine genotype–phenotype associations.