LAUSR

Significance Genetics is a major determining factor in autism spectrum disorder (ASD). To date, only the most severe class of de novo mutation, likely gene disruptive (LGD), has been correlated with IQ, a phenotypic characteristic associated with ASD, but not a core feature. A less severe class of de novo mutation, missense, while enriched in individuals with ASD, has been refractory to correlation with any ASD phenotypic feature. In this report, we demonstrate that de novo LGD and missense mutations scored by target gene vulnerability both show significant associations with diminished motor skills. In individuals with autism spectrum disorder (ASD), de novo mutations have previously been shown to be significantly correlated with lower IQ but not with the core characteristics of ASD: deficits in social communication and interaction and restricted interests and repetitive patterns of behavior. We extend these findings by demonstrating in the Simons Simplex Collection that damaging de novo mutations in ASD individuals are also significantly and convincingly correlated with measures of impaired motor skills. This correlation is not explained by a correlation between IQ and motor skills. 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. We use this finding to propose a combined classification of phenotypic severity: mild (little impairment of either), moderate (impairment mainly to motor skills), and severe (impairment of both IQ and motor skills).