Clinical application of whole exome and genome sequencing in pediatric neurodevelopmental disorders

Neurodevelopmental disorders (NDDs) are frequently encountered in pediatric neurology clinics. However, their extensive genetic heterogeneity often limits the diagnostic yield of standard diagnostic tests, highlighting the need for comprehensive genomic approaches.

This study aimed to evaluate the diagnostic utility of whole exome sequencing (WES) and whole genome sequencing (WGS) in children with unexplained NDDs and assess the clinical relevance of the genomic findings.

We retrospectively reviewed the medical records of 64 pediatric patients with NDDs who underwent WES or WGS between March 2018 and November 2024. Clinical data, neuroimaging and electroencephalography findings, and the results of previous genetic tests were analyzed. The diagnostic yield was calculated, and clinical characteristics were compared between patients with and without a genetically confirmed diagnosis. Patients were categorized as genetically confirmed (positive) when a definitive molecular diagnosis was identified through WES or WGS and as not genetically confirmed (negative) when no causative variant was detected.

A definitive molecular diagnosis was achieved in 25 of 64 patients (39.1%). Diagnostic yields were 37.5% and 33.3% for WES and WGS, respectively. Most variants showed autosomal dominant (n=13) inheritance, followed by X-linked (n=9) and autosomal recessive (n=3) patterns. Novel variants accounted for 57.7% of the pathogenic or likely pathogenic variants. A positive family history was significantly associated with a higher diagnostic yield (20.0% vs. 2.6%, P=0.030), while prematurity was more common in the negative group (33.3% vs. 8.0%, P=0.032). Three WES-negative patients were later diagnosed using chromosomal microarray analysis (CMA) or repeat expansion testing.

WES and WGS are effective diagnostic tools for pediatric NDDs. Phenotype re-evaluation and the selective use of genetic tests such as CMA and repeat expansion analysis enhance diagnostic yield.