CNTNAP2 Heterozygous Missense Variants: Risk Factors for Autism Spectrum Disorder and/or Other Pathologies?

The CNTNAP2 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 Cntnap2 background relevant for CNTNAP2 heterozygosity in patients with ASD. We showed that the cell adhesion glycoprotein Caspr2 encoded by CNTNAP2 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 CNTNAP2 heterozygous and homozygous null mutation may ...