P2.127: Diagnostic Yield of Exome Sequencing for Isolated, Non-Syndromic Autism Spectrum Disorder

Background: Autism spectrum disorder (ASD), a neurodevelopmental disorder (NDD), that affected around 1 in 36 children in the U.S. in 2023. It is characterized by deficits in communication and social interactions. Despite the challenges of elucidating the underlying genetic mechanisms of NDDs due to their broad scope and frequent co-occurrence, genetic testing has proven beneficial for individuals and families by offering insights into medical conditions and enabling tailored clinical management, including referrals to subspecialties, medications, therapies, and monitoring. Fragile X and chromosomal microarray (CMA) testing have historically been the first-line standard of care for ASD. However, only 30.57% of patients with ASD undergo at least one recommended genetic test, despite genetic testing identifying underlying diagnoses in 35% of ASD cases. The existing literature on diagnostic yield of genetic testing for NDDs does not differentiate between yield in “syndromic” vs. “non-syndromic” ASD. This study evaluates the diagnostic yield of exome sequencing (ES) in non-syndromic ASD as it compares to CMA in the same population, aiming to refine genetic testing recommendations.

Methods: A retrospective chart review of patients with ASD seen in a medical genetics clinic from 1/1/2019 to 12/31/2022 was conducted. For the purposes of this study, “non-syndromic” autism was defined as not co-occurring with epilepsy, congenital heart disease, intellectual disability, or central nervous system anomalies. From 1,915 patients identified on initial query of the electronic medical record, 1,259 were classified as syndromic based on these criteria, while the remaining 656 required further classification. The study cohort includes these unclassified patients alongside a random sample of 444 syndromic patients, ensuring 90% power with an alpha of 0.05. Descriptive statistics and t-tests, Wilcoxon Rank Sum tests, chi-squared tests, or Fisher’s exact tests will be used to analyze the data.

Results: Preliminary findings after review of 207 charts reveal overall diagnostic yields of any testing as 23.81% and 5.56% in syndromic and non-syndromic ASD, respectively, with a statistically significant p-value of 0.0006. CMA and ES yields in syndromic ASD were 16.25% and 30.43% (p=0.130), while yields in non-syndromic ASD were 3.53% and 7.69% (p=0.370). Although the difference between CMA and ES yields in non-syndromic ASD was not statistically significant, early data suggest a higher absolute diagnostic yield with ES.

Conclusion: Given the high prevalence of ASD and the increasing accessibility of genetic testing, understanding the diagnostic yield of ES and CMA in non-syndromic ASD is crucial for optimizing healthcare resources and establishing evidence-based best practices. While testing in patients with syndromic ASD has well-established benefits related to medical management and comorbidity identification, the results of this study may help inform future clinical decision-making regarding the utility of genetic testing in non-syndromic ASD, a topic that has yet to be fully elucidated.