Exome Sequencing Comparable to Microarray for Autism Diagnosis, Higher Yield Seen With Appropriate Patient Selection

Diagnostic yields of whole-exome sequencing (WES) and chromosomal microarray analysis (CMA) are comparable among a heterogeneous sample of children with autism spectrum disorder (ASD), according to a study published September 1 in the Journal of the American Medical Association. The combined molecular diagnostic yield of the two technologies was significantly higher in children with more complex morphological phenotypes. The authors say these findings may inform appropriate selection of molecular diagnostic testing for children affected by ASD.

Currently, CMA is the recommended first-tier genetic test for individuals with ASD, with a documented diagnostic yield ranging from 7 percent to 9 percent, while WES is still primarily used in research settings.

In the current study, CMA (for detection of copy-number variants) and WES (for single nucleotide mutation detection) were performed in a heterogeneous group of unrelated children with ASD (all 258 participants for CMA and 95 randomly selected probands with samples from both parents for WES). Targeted-sequencing was conducted in cases of suspected syndromes. The children also underwent detailed assessments to determine the presence of major congenital abnormalities and minor physical anomalies and probands were phenotypically stratified by morphological severity. The complex phenotype was defined as the presence of multiple minor physical anomalies.

The researchers found that the majority of the participants (69.4 percent) were classified as an essential phenotype (no or few physical anomalies), 19.8 percent had equivocal dysmorphology, and 10.9 percent were complex. The diagnostic yield of CMA was 9.3 percent (24 of 258) versus 8.4 percent (8 of 95) from WES (mean coverage depth of 108×; in 9 ASD susceptibility genes, some of which are known to have variable expressivity and penetrance). Among the children who underwent both forms of testing, the estimated proportion with an identifiable genetic etiology was 15.8 percent (15 of 95 children). The yields were statistically different between the morphological groups, with the combined yield significantly higher in the complex group versus the essential group, indicating a higher burden of de novo events in syndromic children. Additionally, incidental or medically actionable findings were reported for 8.4 percent of the participants.

"Our data suggest that medical evaluation of ASD children may help identify populations more likely to achieve a molecular diagnosis with genetic testing," write the authors led by Kristiina Tammimies, Ph.D., from the Hospital for Sick Children in Canada. "Based on analysis of the combined diagnostic yield of CMA and WES, we estimate that more than 35 percent of ASD children with additional medical and dysmorphology features might be able to receive a molecular diagnosis. In contrast, only 6.0 percent of ASD children without syndromic features received a molecular diagnosis."

Several authors report financial ties to SynapDx, which is developing a blood-based test for ASD, but was not involved in this study.

Takeaway: While genetic testing in children with ASD is expected to increase in the coming years, these findings provide initial evidence that appropriate selection of children affected by complex ASD could substantially improve the diagnostic yield.