Genetic Characterization of 128 Chinese Individuals with Neurodevelopmental Disorders via Whole-Exome Sequencing

Neurodevelopmental disorders (NDDs) are chronic conditions marked by abnormal brain development, presenting with significant clinical heterogeneity. Early diagnosis is crucial but challenging due to the complex symptoms. Genetic factors play a dominant role in NDD etiology. This study was to evaluate the diagnostic utility of dual-dimension whole-exome sequencing (WES) analysis in Chinese patients with NDDs and to deepen the understanding of genotype-phenotype correlations.

This study retrospectively analyzed WES data of 128 Chinese NDD patients from Hubei Maternal and Child Health Hospital (July 2020-March 2024) for single-nucleotide variants (SNVs)/small insertions-deletions (Indels) and copy number variants (CNVs). Pathway enrichment, tissue-expression analyses, and functional experiments were conducted to interpret pathogenic genes and variants of uncertain significance.

The overall diagnostic rate for NDDs was 35.9% (46/128), with 28 cases confirmed by SNV/Indel analysis (30 variants in 29 genes) and 18 by CNV analysis (22 variants). Dual-dimension analysis markedly improved the diagnostic rate compared to conventional SNV/Indel analysis (35.9% vs. 21.9%). Patients with multisystem abnormalities had a higher diagnostic rate (63.2% vs. 31.2%). Among the 30 SNV/Indel variants, 86.7% (26) were de novo, and 70.0% (21) were novel. Recurrent pathogenic variants in ASXL3, SHANK3, and EHMT1 genes were identified. Most pathogenic genes were enriched in transcription-regulation pathways and highly expressed in the cerebellum and cerebral cortex. Functional experiments showed that the NLGN3 c.562G>A (p.G188R) hemizygous variant affects protein stability and is deleterious, aiding prenatal diagnosis and the birth of a healthy offspring.

Integrating CNV analysis into routine WES workflows effectively clarifies the genetic heterogeneity of NDDs, expands the gene variant spectrum, and provides a basis for NDD prognosis assessment and precision diagnosis and treatment.