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

Abstract

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.