A number sign (#) is used with this entry because of evidence that developmental and epileptic encephalopathy-74 (DEE74) is caused by heterozygous mutation in the GABRG2 gene (137164) on chromosome 5q34.

Heterozygous mutation in the GABRG2 gene can cause a spectrum of seizure phenotypes, including some with more benign outcomes (see 607681).

Developmental and epileptic encephalopathy-74 (DEE74) is neurologic disorder characterized by the onset of refractory seizures in the first months of life. Seizure types are variable and include infantile spasms, myoclonic, tonic, atonic, and absence, often with secondary generalization. Affected individuals have severe global developmental delay with hypotonia, severe motor impairment, roving eye movements, and absent language (summary by Shen et al., 2017).

For a general phenotypic description and a discussion of genetic heterogeneity of DEE, see 308350.

Shen et al. (2017) reported 8 unrelated children of European descent, ranging in age from 3 to 10 years, with DEE. Onset of variable intractable seizure types occurred in the first year of life, and included tonic-clonic, tonic, partial with secondary generalization, febrile, and myoclonic. The seizures progressed in most patients to include other types. All patients had severe global developmental delay with impaired intellectual development, absent speech, and severe hypotonia with motor disabilities. Additional features included roving or abnormal eye movements, such as nystagmus, and choreiform movements. Brain imaging was normal in most, but 2 patients had volume loss and delayed myelination.

The heterozygous mutations in the GABRG2 gene that were identified in patients with DEE74 by Shen et al. (2017) occurred de novo.

In 8 unrelated children with DEE74, Shen et al. (2017) identified 6 different de novo heterozygous missense mutations in the GABRG2 gene (see, e.g., 137164.0006; 137164.0008-137164.0009). The mutations, which were found by exome or genome sequencing or by sequencing of an epilepsy candidate gene panel, were confirmed by Sanger sequencing. The mutations occurred throughout the gene in different structural domains. Accordingly, in vitro functional expression studies showed variable effects: the variants decreased GABA-evoked currents to different extents and some variants altered zinc sensitivity. Some variants caused reduced potency to GABA stimulation, whereas others caused kinetic abnormalities of the channel. Mutant proteins were stable in transfected HEK293 cells, but showed variably decreased surface and intracellular expression, suggesting impaired trafficking and abnormal retention of some of the mutants in the endoplasmic reticulum. For example, the R323Q mutation (137164.0006), which occurred at an invariant residue in the pore-forming M2 domain, decreased channel current by about 50%, increased zinc inhibition by about 25%, had reduced surface expression (about 50%), and had decreased response to GABA compared to wildtype. The A106T mutation (137164.0007), which occurred in the N-terminal domain, decreased channel current by about 30%, had mildly decreased surface expression (about 75%), slowed deactivation of the channel, and had decreased response to GABA compared to wildtype.