Germline and somatic mutations in with diverse neurodevelopmental phenotypes.

Objective: To expand the clinical phenotype associated with gene mutations and to understand the effect of mutations in the pathogenesis of focal cortical dysplasia (FCD).

Methods: Patients with mutations were identified in various ways: as part of a retrospective cohort study of epileptic encephalopathy; through clinical referrals of individuals (10,619) with developmental delay (DD) for chromosomal microarray; and from a collection of 5,205 individuals with autism spectrum disorder (ASD) examined by whole-genome sequencing.

Results: Seven patients with heterozygous de novo mutations affecting the coding region of were newly identified. Three cases had radiologic evidence suggestive of FCD. One male patient with early infantile epileptic encephalopathy, DD, and ASD achieved complete seizure remission following resection of dysplastic brain tissue. Examination of excised brain tissue identified mosaicism for , providing evidence for a somatic mechanism. Cell-type expression analysis suggested neuron-specific expression. A comprehensive analysis of the published data revealed that 3.1% of severe epilepsy cases carry a pathogenic de novo mutation within By contrast, ASD was rarely associated with mutations in this gene in our large cohorts.

Conclusions: mutations are an important cause of epilepsy and are also rarely associated with ASD. In a case with histologically proven FCD, an somatic mutation was identified, suggesting a role in its etiology. Removing such tissue may be curative for -related epilepsy.