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Numerous studies and case reports show comorbidity of autism and epilepsy, suggesting some common molecular underpinnings of the two phenotypes. However, the relationship between the two, on the molecular level, remains unclear. Here, whole exome sequencing was performed on a family with identical twins affected with autism and severe, intractable seizures. A  de novo  variant was identified in the  KCND2  gene, which encodes the Kv4.2 potassium channel. Kv4.2 is a major pore-forming subunit in somatodendritic subthreshold A-type potassium current ( I SA  ) channels. The  de novo  mutation p.Val404Met is novel and occurs at a highly conserved residue within the  C -terminal end of the transmembrane helix S6 region of the ion permeation pathway. Functional analysis revealed the likely pathogenicity of the variant in that the p.Val404Met mutant construct showed significantly slowed inactivation, either by itself or after equimolar coexpression with the wild-type Kv4.2 channel construct consistent with a dominant effect. Further, the effect of the mutation on closed-state inactivation was evident in the presence of auxiliary subunits that associate with Kv4 subunits to form  I SA   channels  in vivo . Discovery of a functionally relevant novel  de novo  variant, coupled with physiological evidence that the mutant protein disrupts potassium current inactivation, strongly supports  KCND2  as the causal gene for epilepsy in this family. Interaction of  KCND2  with other genes implicated in autism and the role of  KCND2  in synaptic plasticity provide suggestive evidence of an etiological role in autism.

human molecular genetics

Exome sequencing identifies  de novo  gain of function missense mutation in  KCND2  in identical twins with autism and seizures that slows potassium channel inactivation