Analysis Suggests Genome Sequencing as First-Tier Diagnostic for Autism, Fetal Structural Anomalies

Genome sequencing should be considered as a first-tier diagnostic approach for autism spectrum disorder (ASD) and fetal structural anomalies (FSAs), researchers from Massachusetts General Hospital and elsewhere report in the American Journal of Human Genetics. In their study, they compared the diagnostic yield of short-read genome sequencing to that of the current standard-of-care approaches — karyotyping, chromosomal microarray, and exome sequencing — for ASD and FSAs. In their cohort of 1,612 quartet families with members with ASD, the researchers found that genome sequencing identified a diagnostic variant in 7.8 percent of probands, nearly twice what chromosomal microarrays and exome sequencing found, though the diagnostic yield of exome sequencing improved when a method to capture CNVs was applied. Meanwhile, in their 249 fetus-parent trio cohort, sequencing had a diagnostic yield of 46.1 percent, an improvement of 17.2 percent over karyotyping, 14.1 percent over chromosomal microarrays, 38.3 percent over exome sequencing, and 4.1 percent over exome sequencing with CNV identification. "Overall, these data suggest that [genome sequencing] can effectively displace karyotype, CMA, and ES as a single diagnostic test for the assessment of FSAs and ASD and will provide a marginal, but important, increase in diagnostic yield beyond the combination of all three current standard-of-care diagnostic tests," the researchers write.