Abstracts

Rationale: The epilepsy-aphasia spectrum (EAS) refers to a complex group of epilepsy syndromes associated with language impairment and variable outcome. On the severe end of the spectrum is Landau-Kleffner syndrome (LKS) and epileptic encephalopathy with continuous spike-and-wave during sleep syndrome (ECSWS) which often carry a poor prognosis including impaired cognitive function with speech and language difficulties. Related to the EAS from an electroencephalographic perspective but without major cognitive problems is the mild epilepsy syndrome of childhood epilepsy with centrotemporal spikes (CECTS). CECTS is the most common focal epilepsy in children and carries an excellent prognosis. It is unknown whether there is a common underlying mechanism to syndromes lying along the EAS. A genetic basis was not suspected until recently with the discovery that copy number variations (CNVs) and mutations in GRIN2A cause 5-20% of cases of dominant familial and sporadic EAS. We sought to identify novel genetic causes of sporadic EAS through whole-exome sequencing. Methods: Whole exome sequencing was performed in 16 proband-parent trios and a single proband-mother duo. We prioritized the following genotypes for review of their relevance to EAS: de novo mutations and/or parental mosaic variants, compound heterozygous, newly homozygous, and X-linked hemizygous genotypes. Results: We identified pathogenic or likely pathogenic de novo variants in 3/17 probands providing a potential molecular diagnosis for 18% of the cohort. The de novo variants in these three individuals were in FOXP1, KCNMA1, and SETD1B. No single gene was responsible for multiple cases, nor did the genes converge on a single molecular pathway. We also identified potentially pathogenic variants in 5 candidate genes (CSNK1D, ATP1A2, PPFIA3, DEPTOR, NCAPG2). Targeted sequencing of these 8 genes in a cohort of 525 probands with diverse developmental and epileptic encephalopathies did not yield any additional pathogenic variants.  Conclusions: We expand our understanding of the genes associated with EAS and highlight the genetic heterogeneity of these severe disorders. We provide important phenotype expansion of the recently discovered neurodevelopmental genes FOXP1, KCNMA1, and SETD1B. Funding: C.T.M. is supported by postdoctoral fellowships from the Lennox-Gaustaut Syndrome Foundation (LGSF) and the American Epilepsy Society.