Genetic Diagnostic Yield in Autism Spectrum Disorder (ASD) and Epilepsy Phenotypes in Children with Genetically...

Area of Science:

• Neurogenetics
• Developmental Pediatrics
• Clinical Genetics

Background:

• Autism spectrum disorder (ASD) is a complex neurodevelopmental condition with a significant genetic component.
• Identifying genetic causes of ASD is crucial for understanding disease mechanisms and improving clinical management.
• Epilepsy is a common comorbidity in ASD, and its relationship with genetic diagnoses requires further investigation.

Purpose of the Study:

• To compare epilepsy phenotypes in children with genetically defined versus undefined autism spectrum disorder (ASD).
• To evaluate the diagnostic yield of different genetic testing modalities in children with ASD.
• To investigate the association between genetic diagnosis in ASD and specific clinical features, including epilepsy.

Main Methods:

• A single-center retrospective study included 523 patients with ASD who underwent genetic testing.
• Patients were classified as having genetically defined ASD based on updated genotype-phenotype correlations.
• Diagnostic yields of whole exome sequencing (WES) and chromosomal microarray (CMA) were compared.

Main Results:

• Overall, 15.1% of patients received a genetic explanation for their ASD diagnosis.
• WES demonstrated a higher diagnostic yield (23.0%) compared to CMA (8.3%).
• Children with genetically defined ASD exhibited higher rates of microcephaly, hypotonia, dysmorphic features, developmental delay/regression, and significantly higher prevalence of epilepsy (35.4% vs. 16.4%).
• Genetically defined ASD was associated with an earlier age of epilepsy onset (median 2.2 vs. 5.0 years) and a trend towards higher rates of drug-resistant epilepsy.

Conclusions:

• Whole exome sequencing (WES) should be considered a first-tier genetic testing approach for children with ASD.
• An early genetic diagnosis in ASD can inform surveillance and management of comorbid conditions, particularly epilepsy.
• Genetically defined ASD is linked to distinct phenotypic features and a higher burden of epilepsy, underscoring the importance of genetic evaluation.