New Genes for Epilepsy–Autism Comorbidity

Abstract

AbstractSimilar genetic abnormalities have been demonstrated for epilepsy and autism spectrum disorder (ASD). Genetic syndromes, such as fragile X syndrome and tuberous sclerosis, also have high rates of comorbidity with epilepsy and ASD. Furthermore, next-generation sequencing has identified common genetic abnormalities in epilepsy and ASD, and recurrent de novo gene alterations can be recognized as mutations if there is sufficient evidence for pathogenicity. Such mutations occur in SCN2A and GRIN2B. SCN2A encodes the α2 subunit of the Nav1.2 neuronal voltage-gated Na+ channel, which is mutated in several genetically mediated epilepsies. GRIN2B encodes a subtype of the N-methyl-D-aspartate glutamate receptor and is mutated in epileptic encephalopathies, which often present with features of ASD. In addition, KCNT1 encodes the Na+-dependent K+ channel known as Slack. Mutations in KCNT1 produce several epilepsy phenotypes, including autosomal dominant frontal lobe epilepsy, which often includes features of ASD. Slack also has an intracellular fragile X mental retardation protein-binding domain, which is significant in its relationship with intellectual disabilities. Furthermore, DEPDC5 mutations produce autosomal dominant familial focal epilepsy with variable foci and may contribute to ASD. DEPDC5 encodes a regulator of the mechanistic target of rapamycin (mTOR) pathway, which is also affected by tuberous sclerosis mutations, suggesting that “mTORopathy” may underlie both epilepsy and ASD. Mutations in PCDH19 also produce an epilepsy syndrome that exclusively affects heterozygous females and is associated with ASD. The genetic similarities between ASD and epilepsy provide insight into the pathological molecular mechanisms of both conditions and therefore may be useful for understanding clinical outcomes.