2 research outputs found
Rare variants in the GABAA receptor subunit ε identified in patients with a wide spectrum of epileptic phenotypes
Background: Epilepsy belongs to a group of chronic and highly heterogeneous brain
disorders. Many types of epilepsy and epileptic syndromes are caused by genetic
factors.
The neural amino acid y-aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the mammalian central nervous system. It regulates activity of channel pores
by binding to transmembrane GABA-receptors (GABRs). The GABRs are heteropentamers assembled from different receptor subunits (α1-6, β1-3, γ1-3, δ, ε, θ, π, and
ρ1-3). Several epileptic disorders are caused by mutations in genes encoding single
GABRs.
Methods: We applied trio- and single-whole exome sequencing to search for genetic
sequence variants associated with a wide range of epileptic phenotypes accompanied
by intellectual disability and/or global developmental delay in the investigated patients.
Results: We identified four hemizygous sequence variants in the GABAA receptor subunit ε gene (GABRE), including one nonsense (NM_004961.3: c.399C>A, p.Tyr133*), two missense variants (NM_004961.3: c.664G>A, p.Glu222Lys; NM_004961.3:
c.1045G>A, p.Val349Ile), and one variant affecting the translation initiation codon
(NM_004961.3: c.1A>G, p.Met1?) in four unrelated families.
Conclusion: Our clinical and molecular genetic findings suggest that GABRE is a
likely candidate gene for epilepsy. Nevertheless, functional studies are necessary to
better understand pathogenicity of the GABRE-mutations and their associations with
epileptic phenotypes
Genetic and phenotypic heterogeneity suggest therapeutic implications in SCN2A-related disorders
Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatm