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

Researchers studied 523 children with autism to compare different genetic tests and look at seizure patterns. They found that a more comprehensive genetic test (whole exome sequencing) was better at finding genetic causes than simpler tests. About 15% of children had a genetic cause identified. Children with genetic causes of autism were more likely to have seizures (35% vs 16%), and their seizures started earlier (around age 2 vs age 5).

These children also had more physical features like smaller heads and muscle weakness.

This retrospective study of 523 children with autism spectrum disorder (ASD) investigated genetic testing diagnostic yields and epilepsy phenotypes. Whole exome sequencing (WES) demonstrated superior diagnostic yield compared to chromosomal microarray (23.0% vs 8.3%). Overall, 15.1% of children received a genetic diagnosis explaining their ASD. Children with genetically defined ASD showed significantly higher rates of microcephaly, hypotonia, dysmorphic features, and developmental delay/regression.

Notably, epilepsy prevalence was significantly higher in genetically defined ASD (35.4% vs 16.4%), with earlier onset (median 2.2 vs 5.0 years) and trends toward increased drug resistance. The findings support WES as first-tier genetic testing for ASD and highlight the importance of early genetic diagnosis for informing surveillance and management of comorbid conditions.

WES should be considered first-tier genetic testing for ASD. Early genetic diagnosis enables proactive epilepsy monitoring and management planning. Children with genetic ASD diagnoses require enhanced surveillance for seizures, particularly in early childhood. Physical phenotyping can inform genetic testing decisions and comprehensive care approaches.

Single-center retrospective design limits generalizability. Sample size for specific genetic variants not detailed. Drug-resistant epilepsy comparison did not reach statistical significance. Long-term outcomes and management responses not assessed.

We compared the epilepsy phenotypes in children with genetically defined versus undefined autism spectrum disorder (ASD). A single-center retrospective study was conducted to investigate diagnostic yields of different genetic testing for children with ASD. Patients with at least one testing modality were included and classified as having genetically defined ASD or not based on updated genotype-phenotype correlation. Of the 523 patients included, 79 (15.1%) had results explaining their ASD diagnosis.

WES (whole exome sequencing) outperformed CMA (chromosomal microarray) on diagnostic yield (23.0% versus 8.3%). Compared to those with non-diagnostic test(s), children with genetically defined ASD were associated with higher rates for microcephaly, hypotonia, dysmorphic features, and developmental delay/regression. The prevalence of epilepsy was significantly higher in children with genetically defined ASD than those without a genetic diagnosis (35.4% versus 16.4%, p < 0.001, power = 0.97). Furthermore, children with genetically defined ASD had a younger age of epilepsy onset (median 2.2 versus 5.0 years, p = 0.002, power = 0.90) and a higher rate of drug-resistant epilepsy although not reaching statistical significance (35.7% versus 21.9%, p = 0.20).

Our study has provided further evidence to support WES as first-tier test for children with ASD and that an early genetic diagnosis has the potential to inform further surveillance and management for ASD comorbid conditions including epilepsy.