De novo GABRA1 mutations in Ohtahara and West syndromes

Epilepsia. 2016 Apr;57(4):566-73. doi: 10.1111/epi.13344. Epub 2016 Feb 25.


Objective: GABRA1 mutations have been identified in patients with familial juvenile myoclonic epilepsy, sporadic childhood absence epilepsy, and idiopathic familial generalized epilepsy. In addition, de novo GABRA1 mutations were recently reported in a patient with infantile spasms and four patients with Dravet syndrome. Those reports suggest that GABRA1 mutations are associated with infantile epilepsy including early onset epileptic encephalopathies. In this study, we searched for GABRA1 mutations in patients with infantile epilepsy to investigate the phenotypic spectrum of GABRA1 mutations.

Methods: In total, 526 and 145 patients with infantile epilepsy were analyzed by whole-exome sequencing and GABRA1-targeted resequencing, respectively.

Results: We identified five de novo missense GABRA1 mutations in six unrelated patients. A p.R112Q mutation in the long extracellular N-terminus was identified in a patient with infantile epilepsy; p.P260L, p.M263T, and p.M263I in transmembrane spanning domain 1 (TM1) were identified in three unrelated patients with West syndrome and a patient with Ohtahara syndrome, respectively; and p.V287L in TM2 was identified in a patient with unclassified early onset epileptic encephalopathy. Four of these mutations have not been observed previously.

Significance: Our study suggests that de novo GABRA1 mutations can cause early onset epileptic encephalopathies, including Ohtahara syndrome and West syndrome.

Keywords: De novo mutation; Early onset epileptic encephalopathy; GABAA receptor; GABRA1; Infantile epilepsy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Child
  • Child, Preschool
  • Electroencephalography
  • Female
  • Humans
  • Infant
  • Male
  • Molecular Sequence Data
  • Mutation, Missense / genetics*
  • Receptors, GABA-A / genetics*
  • Spasms, Infantile / diagnosis*
  • Spasms, Infantile / genetics*
  • Spasms, Infantile / physiopathology


  • GABRA1 protein, human
  • Receptors, GABA-A