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Autism Analysis Uncovers Ties Between Motor Skills, Damaging De Novo Mutations

NEW YORK (GenomeWeb) – The preponderance of de novo mutations that occur in some individuals with autism spectrum disorder (ASD) may include damaging mutations that appear to impact motor skills, new research suggests.

In an early, online study in the Proceedings of the National Academy of Sciences, researchers from the Cold Spring Harbor Laboratory (CSHL), New York Genome Center (NYGC), and elsewhere used available exome sequence, clinical, and behavioral data for participants in the Simons Simplex Collection (SSC) — a set of families that includes one child with ASD — to track the consequences of de novo mutations in children with ASD.

The effort "is part of our continuing attempt to link damaging de novo mutations to broad neuropsychiatric effects in children on the autism spectrum," corresponding author Michael Wigler, a researcher affiliated with both CSHL and the NYGC, and his colleagues wrote. "We have done this both to define the substructure of the syndrome and to evaluate which events are likely to contribute to the disorder."

The team noted that damaging mutations have been linked to lower-than-usual non-verbal IQ levels in past studies of ASD. The latest work expands on those findings, uncovering independent ties between reduced motor skills in ASD and the presence of likely gene disruptive or missense de novo mutations in the genomes of affected individuals.

For their analysis, the researchers tapped into SSC data for 2,760 families, including 2,280 families with an ASD-affected child and at least one unaffected sibling. The available exome sequence data for 2,446 participants with ASD revealed more than 3,400 de novo mutations, while almost 2,300 de novo mutations turned up in exome sequences from 1,836 of the children without ASD.

In most cases, the team also had access to behavioral data for children with ASD, including their fine and gross motor skills, based on parental surveys such as the Developmental Coordination Disorder Questionnaire.

From there, the researchers considered phenotypes such as movement, coordination, fine motor skills, or handwriting ability alongside de novo mutation profiles in individuals with ASD, focusing on the likely gene disruptive or missense de novo mutations. In a set of 352 likely gene disruptive mutations, for example, they identified 57 recurrent mutations — a set of de novo mutations that was significantly associated with behavioral features reported on the parental questionnaires.

Consistent with prior studies, the team saw ties between decreased IQ and likely gene disruptive de novo mutations in genes targeted by the fragile X mental retardation protein.

Mutations in these and other gene types also corresponded with poorer motor skills such as first walking age, they reported. Similar motor skill associations turned up when they considered missense de novo mutations, including some missense mutations in genes not implicated in non-verbal IQ.

"We find that IQ and motor skills are distinctly associated with damaging mutations and, in particular, that motor skills are a more sensitive indicator of mutational severity than is IQ, as judged by mutational type and target gene," the authors wrote.