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Keywords: Autism; Genetic testing; Intellectual and developmental disability; Exome sequencing; Neurogenetics

T. Brandt; A. Shanmugham; J. Scuffins; J. Juusola; D. McKnight

Affiliation: Gene Dx, Gaithersburg, Maryland.

Autism spectrum disorders (ASD) and intellectual disability (ID) are common and frequently co-morbid disorders with a high degree of genetic heterogeneity. Exome sequencing is reported to have a positive diagnostic result (PDR) of ~14-33% for ASD/ID cohorts. However, studies demonstrating the utility of genetic testing for subgroups of patients within this wide phenotypic spectrum are rare. The objective of this study was to determine the utility of genetic testing for patients with ASD and/or ID. This is a retrospective study of genetic testing results of 2,497 patients with ASD/ID/developmental delay referred to our clinical laboratory. For each of these patients, 2,300+ genes associated with ASD and/or ID were sequenced and analyzed. The PDR for all cases was ~16%; however, the PDR varied depending on the clinical information provided. Patients with ID and multiple additional malformations or other significant medical issues (e.g. dysmorphic features, seizures, hypotonia), but not autistic features, had the highest PDR (~36%, 46/128), whereas patients with autistic features and multiple additional medical issues in the absence of ID had a significantly lower PDR (~15%, 57/386, p<0.0001). Patients with isolated ID or ASD had a PDR of ~23% (10/44) and ~4% (19/492), respectively. The PDR for patients <2 years old with developmental delays was ~27% (27/99). High genetic heterogeneity was observed among positive cases; however, 22 different genes were responsible for >40% of positive cases. In summary, genetic testing for patients with ID and additional major medical issues revealed a genetic etiology of disease in over one-third of cases. A genetic etiology was less likely to be identified in patients with ASD. The presence of additional phenotypic findings did correlate with an increased PDR. Therefore, this study supports the hypothesis that monogenic etiologies are relatively uncommon findings in patients with isolated ASD. In addition, although there is vast genetic heterogeneity for ID and ASD, findings in just over 20 genes accounted for a significant portion of positive cases, suggesting a minimum number of genes that should be tested for these patients.