Neurodevelopmental Phenotypes and Brain Anomalies in Individuals With Heterozygous SEMA6A Variants.

SEMA6A is a transmembrane protein that plays a role in axon guidance and cell migration. Sema6a null mice have cerebral anatomical defects and altered social interactions and working memory. However, the phenotypes associated with loss of SEMA6A function have not been clearly defined in humans. Here we describe 11 individuals who are heterozygous for putatively damaging variants affecting SEMA6A. All of these individuals (100%) had neurodevelopmental phenotypes that included developmental delay, intellectual disability, and/or autism spectrum disorder. Abnormal behaviors were seen in 73% with oppositional defiant disorder being diagnosed in 27% and acting out, overeating, and tantrums each being described in 18% of individuals. Disorders of attention were documented in 45%. Among the six individuals who had a brain MRI, 50% had at least one abnormal finding. Of the eight SEMA6A variants with known inheritance, five were inherited. Taken together, our data suggest that loss of SEMA6A function may be associated with an increased risk of neurodevelopmental phenotypes, abnormal behaviors, disorders of attention, and brain anomalies. Additional studies will be needed to determine if SEMA6A haploinsufficiency is best characterized as an autosomal dominant disorder with incomplete penetrance or as a risk factor for these phenotypes.