Delayed Walking May Signal Spontaneous Gene Anomalies in Autism

Distinct Behavioral Profiles Linked to “High Confidence” ASD Risk Genes

BY JULES ASHER, NIMH

A team of National Institute of Mental Health (NIMH) intramural and grant-supported researchers has discovered a pattern of behavioral and genetic features seen in some cases of autism spectrum disorder (ASD) that could ultimately lead to identification of subgroups and improved treatment.

Children diagnosed with ASD who had spontaneous, noninherited changes in autism-linked genes showed “muted” core autism symptoms related to social behavior and language compared with sex-, age-, and IQ-matched children with ASD without known genetic abnormalities. A key clue was that children with the spontaneous glitches—abnormal numbers of copies of genes or other mutations linked to functional impairments—tended to start walking later than usual, which is not typical of children with ASD. In fact, the odds of a child in this sample having a spontaneous abnormal gene finding increased by 17 percent for each month of delay in walking.

“Identifying individuals whose ASD is associated with a specific type of genetic abnormality may lead us to distinct processes ultimately traceable to specific causes, which could be targeted by more personalized interventions,” explained NIMH intramural researcher Audrey Thurm. “In the meantime, our results can increase awareness that among children with an ASD diagnosis, certain characteristics [such as] late walking are associated with genetic abnormalities.”

Thurm, NIMH grant–supported researcher Somer Bishop of the University of California at San Francisco, and colleagues reported their identification of an emerging cluster of developmental, behavioral, and genetic markers in ASD on March 3, 2017, in the American Journal of Psychiatry (Am J Psychiatry, DOI:10.1176/appi.ajp.2017.16101115).

Before the study, the estimated 10 to 15 percent of children with ASD who have noninherited, or de novo, gene-copy-number variations or suspected disrupting, severe mutations had not been found to show specific patterns of ASD-related symptoms or delays in developmental milestones. The new discovery was made possible through advances in genomics technology, allowing for a large number of “high-confidence” suspect genes to be identified, as well as more rigorous matching of children with and without genetic abnormalities than in previous studies. For example, the new study controlled for the potentially confounding effects of IQ, which has been previously found to be lower in children with ASD with de novo mutations.

Results showed that children with de novo mutations tended to be less impaired on core ASD symptoms than their peers with more typical ASD and no known genetic abnormalities. Children with de novo mutations also tended to have stronger verbal, language, and social-communication abilities, and clinicians involved in assessing the children were less confident in their ASD diagnoses for the subgroup with de novo mutations. Yet children with de novo mutations began walking, on average, at 19 months, compared with 13.6 months for children with typical ASD, when controlling for differences in nonverbal IQ.

“While all children in this study met diagnostic criteria for ASD, those with genetic abnormalities showed subtle, yet potentially important, differences in their behavioral profiles when compared to appropriately matched children with no such abnormalities,” said Bishop. “These findings are in line with previous assertions that, as a group, de novo mutations may be best understood as conferring risk for neurodevelopmental problems more generally, rather than ASD core symptoms specifically.”

This article first appeared on the NIMH science news website.