Target resequencing of epilepsy candidate genes helps expand phenotype

In data was presented at the 2015 American Epilepsy Society Annual Meeting, Candace Myers, PhD, of the University of Washington, and colleagues have shown that targeted high throughput resequencing of genes in which a de novo mutation was previously been identified can help expand the phenotypic spectrum associated with these genes.

They sought to expand on their previous study where they identified 329 de novo mutations in 305 genes when 264 trios (affected child and unaffected parents).
For their current study the researchers performed targeted capture and high-throughput resequencing of 27 genes in which a de novo mutation was identified in one or more proband with Infantile Spasms (IS) or Lennox-Gastaut syndrome (LGS) in our prior study. 537 patients with diverse Epileptic Encephalopathy phenotypes were screened.

They were able to confirm the role of at least 7 additional genes in the genetic etiology of EE and expand the phenotypic spectrum associated with these genes beyond IS and LGS in which they were first discovered.

Among the genes identified there were recurrent and novel mutations in ALG13, CACNA1A, DNM1, GABRB3, GNAO1, IQSEC2, and SLC1A2 highlighting the importance of these genes in Epileptic Encephalopathies. Interestingly, 44% of the pathogenic variants identified in this study were recurrent mutations.

In addition they also identified a parent with a mosaic germline mutation in the case of two independent families with multiple affected individuals. GABRB3 accounted for the majority of pathogenic variants (n=6/537), accounting for ~1% of our cohort.

Citation: Myers C, McMahon J, Schneider A, et al. Abstract 1.315. Gene discovery in epileptic encephalopathies through targeted resequencing of candidate genes. Presented at: American Epilepsy Society Annual Meeting. Dec 4-8; Philadelphia.