About this item:

165 Views | 148 Downloads

Author Notes:

Corresponding Author: Andrew Escayg, Ph.D., Department of Human Genetics, Emory University, Atlanta, Georgia 30322, aescayg@emory.edu , Phone: 404-712-8328, Fax: 404-727-3949

We would like to thank the families for their participation.

We are grateful for the assistance of Cynthia Freehauf in the collection of clinical data.

Deep amplicon sequencing was performed by the Emory Integrated Genomics Core (EIGC), which is subsidized by the Emory University School of Medicine and is one of the Emory Integrated Core Facilities.

Subjects:

Research Funding:

This study was supported by funding from Children’s Healthcare of Atlanta to A.E., the Emory University Research Council to A.E. and J.J.A., and a training grant appointment (5T32GM008490-23) to K.M.B.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Clinical Neurology
  • Neurosciences & Neurology
  • SCN8A
  • Sodium channels
  • Epilepsy
  • Gene panel analysis
  • SODIUM-CHANNEL SCN8A
  • SEVERE MYOCLONIC EPILEPSY
  • INTELLECTUAL DISABILITY
  • SPECTRUM DISORDERS
  • INFANTILE SEIZURES
  • ENCEPHALOPATHY
  • INACTIVATION
  • NA(V)1.6
  • RECURRENT
  • INFANCY

De novo and inherited SCN8A epilepsy mutations detected by gene panel analysis

Tools:

Journal Title:

Epilepsy Research

Volume:

Volume 129

Publisher:

, Pages 17-25

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Objectives To determine the incidence of pathogenic SCN8A variants in a cohort of epilepsy patients referred for clinical genetic testing. We also investigated the contribution of SCN8A to autism spectrum disorder, intellectual disability, and neuromuscular disorders in individuals referred for clinical genetic testing at the same testing laboratory. Methods Sequence data from 275 epilepsy panels screened by Emory Genetics Laboratory were reviewed for variants in SCN8A. Two additional cases with variants in SCN8A were ascertained from other testing laboratories. Parental samples were tested for variant segregation and clinical histories were examined. SCN8A variants detected from gene panel analyses for autism spectrum disorder, intellectual disability, and neuromuscular disorders were also examined. Results Five variants in SCN8A were identified in five individuals with epilepsy. Three variants were de novo, one was inherited from an affected parent, and one was inherited from an unaffected parent. Four of the individuals have epilepsy and developmental delay/intellectual disability. The remaining individual has a milder epilepsy presentation without cognitive impairment. We also identified an amino acid substitution at an evolutionarily conserved SCN8A residue in a patient who was screened on the autism spectrum disorder panel. Additionally, we examined the distribution of pathogenic SCN8A variants across the Na v 1.6 channel and identified four distinct clusters of variants. These clusters are primarily located in regions of the channel that are important for the kinetics of channel inactivation. Conclusions Variants in SCN8A may be responsible for a spectrum of epilepsies as well as other neurodevelopmental disorders without seizures. The predominant pathogenic mechanism appears to involve disruption of channel inactivation, leading to gain-of-function effects.

Copyright information:

© 2016 Elsevier B.V. All rights reserved.

Export to EndNote