Whole-Exome Sequencing Identifies Novel Genetic Variants Associated with Unexplained Neurodevelopmental Disorders in Children

TL;DR

Whole-exome sequencing helps find new genetic variants linked to unexplained neurodevelopmental disorders in children.

Contribution

The study identifies novel genetic variants and demonstrates the utility of CAST in detecting rare variant enrichment in NDD cases.

Findings

WES identified 12 pathogenic and 16 likely pathogenic variants in children with NDDs.

CAST revealed rare variant enrichment in genes related to neuronal development in affected individuals.

Abstract

Neurodevelopmental disorders (NDDs) are a heterogeneous group of conditions characterised by impairments in cognition, motor function, behaviour, and social interaction. Their genetic basis is highly diverse, and next-generation sequencing has become central to improving diagnostic yield. We retrospectively analysed 94 paediatric patients (0–18 years) with NDDs referred to the Paediatric and Rare Diseases Clinic, Microcitemico Hospital “A. Cao,” between January 2019 and July 2024. Each patient underwent detailed clinical evaluation and whole-exome sequencing (WES). Variants were prioritised according to ACMG guidelines. Gene burden analysis of rare predicted loss-of-function variants was performed using the Cohort Allelic Sums Test to detect enrichment in NDD cases relative to controls. WES identified 12 pathogenic variants, 16 likely pathogenic variants, and 10 variants of uncertain significance. Autosomal dominant disorders were the most frequent (n = 35 patients), while autosomal recessive and X-linked dominant conditions were identified in a single case each. The findings of this study further highlight the importance of WES in identifying novel genetic variants and in providing explanations for previously unexplained NDD cases. Moreover, the Cohort Allelic Sums Test (CAST) demonstrated that rare variants are enriched in genes implicated in neuronal development in affected individuals.

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