Genetic testing in patients with nonsyndromic autism spectrum disorder and EEG abnormalities with or without epilepsy: Is exome trio-based testing the best clinical approach?

Abstract

Objectives: The association between autism spectrum disorder (ASD) and epilepsy is well-known. Abnormalities on electroencephalography (EEG) studies have been reported in patients with ASD without a history of seizures, and these patients have lower functional scores on adaptive measures than patients with ASD with normal EEG studies. The purpose of the study was to evaluate the genetic test approach in children with ASD and abnormal EEGs.

Methods: Data were collected from medical records at Cincinnati Children's Hospital Medical Center (CCHMC) of a previously published cohort of patients with well-characterized ASD based on evaluation by Developmental Pediatrics. Patients were subdivided into two groups: ASD without epilepsy, but with abnormal EEG results, and ASD with epilepsy. EEG data were abstracted from reports. In this follow-up study, we analyzed genetic testing data, namely the proportion of this cohort that received genetic testing, and the specific type of genetic testing that was ordered to analyze if there were any differences between groups.

Results: Analysis was performed on 173 patients with ASD. Ninety-five patients had a diagnosis of epilepsy. Seventy-eight patients did not have a diagnosis of epilepsy but did have abnormal EEGs. In both groups, approximately three quarters of all subjects received routine neurodevelopmental genetic testing (77% versus 72% p = 0.15) without significant differences between groups. The ASD + epilepsy group was more likely to receive additional second-tier genetic testing outside of a routine neurodevelopmental workup (35% versus 15% p = 0.007). The ASD + epilepsy group was more likely to receive phenotype specific panels, most often an epilepsy gene panel of less than 250 genes (15% versus 3% p = 0.008). However, the ASD + epilepsy group was less likely to receive a genetic diagnosis from testing than the ASD + abnormal EEG group (9% versus 33%, p = 0.047).

Conclusions: Patients with ASD along with a formal epilepsy diagnosis received more genetic testing; but had an overall lower diagnostic rate than patients with ASD with abnormal EEGs but without a formal epilepsy diagnosis. Patients in this cohort without a diagnosis of epilepsy were more likely to get broad trio-based exome testing instead of targeted epilepsy gene panel testing. A higher diagnostic rate was found in patients when a broad genetic test strategy was implemented.

Keywords: Autism; Epilepsy; Exome; Neurodevelopmental disorders.