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

Area of Science:

• Genetics
• Pediatrics
• Neuroscience

Background:

• Neurodevelopmental disorders (NDDs) present diverse clinical features affecting cognition, motor skills, behavior, and social interaction.
• The genetic underpinnings of NDDs are complex, necessitating advanced diagnostic tools like next-generation sequencing.

Purpose of the Study:

• To evaluate the diagnostic utility of whole-exome sequencing (WES) in pediatric patients with unexplained NDDs.
• To identify genetic variants associated with NDDs using WES and gene burden analysis.

Main Methods:

• Retrospective analysis of 94 pediatric patients (0-18 years) with NDDs.
• Clinical evaluation and whole-exome sequencing (WES) followed by variant prioritization using ACMG guidelines.
• Gene burden analysis using the Cohort Allelic Sums Test (CAST) to assess variant enrichment in NDD cases.

Main Results:

• WES identified 12 pathogenic, 16 likely pathogenic, and 10 variants of uncertain significance.
• Autosomal dominant disorders were most common (35 patients); single cases of autosomal recessive and X-linked dominant disorders were found.
• CAST revealed enrichment of rare variants in genes crucial for neuronal development among affected individuals.

Conclusions:

• WES is a valuable tool for diagnosing previously unexplained NDD cases in pediatric populations.
• The study underscores the role of rare variants in genes associated with neuronal development in the etiology of NDDs.
• Integration of WES with gene burden analysis enhances diagnostic yield for complex neurodevelopmental conditions.