Heterozygous Missense Variants: Risk Factors for Autism Spectrum Disorder and/or Other Pathologies?

The gene has been proposed to be one of the major susceptibility genes for neurodevelopmental disorders, in which numerous heterozygous missense variants have been identified in patients with autism spectrum disorder (ASD). The contribution of these variants to the manifestations of ASD is however highly controversial because numerous heterozygous missense variants have also been identified in control subjects. In a recent study, we set up a sensitive developmental in vitro cell assay to clarify the potential functional impact of these variants in a heterozygous background relevant for heterozygosity in patients with ASD. We showed that the cell adhesion glycoprotein Caspr2 encoded by plays a dose-dependent role in cortical neuron axon growth and provided a proof of principle that some variants have functional consequences, either a loss of function or a dominant-negative effect. This indicates that phenotypes mimicking heterozygous and homozygous null mutation may exist in humans. Our observations further suggest that more variants than originally expected could be functionally deleterious and induce a high heterogeneity of phenotypes at the scale of the whole brain. This raises the interesting possibility that heterozygous missense variants could define an overall endophenotype shaping a risk for ASD and questions whether, beyond ASD, the variants could contribute to the development of other neurodevelopmental disorders and/or genetically less complex pathologies.