Generalized Epilepsy With Febrile Seizures Plus via the GABRG2 Gene

Idiopathic generalized epilepsy (IGE) is a clinically and genetically heterogeneous group of epilepsy disorders. IGE has a strong genetic basis, is not usually associated with cognitive defects and presents during childhood or adolescence. Sub-types of IGE include: juvenile myoclonic epilepsy (JME), childhood absence epilepsy (CAE), and generalized epilepsy with febrile seizures plus (GEFS+).

GEFS+ patients usually present with fever induced seizures between the ages of 6 months and 6 years. 'Plus' refers to the persistence of seizures into adolescence, when patients may also experience myoclonic, absence or focal seizures (Audenaert et al. 2006).

GEFS+ is inherited in an autosomal dominant manner and can be caused by mutations in the GABRG2 gene. Both missense and nonsense mutations in GABRG2 have been reported in cases of GEFS+. The penetrance of GABRG2 mutations is incomplete (Lachance-Touchette et al. 2011).

The GABRG2 gene encodes a subunit of the neuronally expressed GABAA receptor. GABA is an inhibitory neurotransmitter responsible for modulating signaling in the brain. Mutations in GABAA receptor subunits decrease the receptor's response to GABA, thus reducing GABA-signaling. It is proposed that this loss of inhibition in neurons results in increased synaptic excitation and epilepsy (Lachance-Touchette et al. 2011). It has been demonstrated that some mutations in GABRG2 are especially sensitive to elevated temperature, hence their association with febrile seizures (Kang et al. 2006).

GABRG2 mutations account for ~3-4% of GEFS+ cases and ~1% of IGE cases (Sun et al. 2008; Audenaert et al. 2006; Lachance-Touchette et al. 2011).

This test provides full coverage of all coding exons of the GABRG2 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.