Phenotypic Spectrum in Individuals With Pathogenic GABRG2 Loss- and Gain-of-Function Variants.

Area of Science:

• Neurogenetics
• Epilepsy Pathophysiology
• Molecular Neuroscience

Background:

• Pathogenic variants in the GABRG2 gene are linked to a wide range of epilepsy syndromes, from febrile seizures to developmental and epileptic encephalopathies (DEEs).
• Previous studies suggested loss-of-function (LoF) as a mechanism, but the precise relationship between GABRG2 variant function and diverse clinical presentations remained unclear.

Purpose of the Study:

• To investigate the functional consequences of GABRG2 variants.
• To correlate these functional changes with the spectrum of epilepsy phenotypes observed in affected individuals.

Main Methods:

• Systematic collection of electroclinical data from individuals with GABRG2 variants.
• Electrophysiologic functional assessments of missense GABRG2 variants to determine their impact on receptor function (LoF or GoF).

Main Results:

• Analysis of 35 GABRG2 variants in 44 individuals revealed 18 null variants, 17 missense variants (9 LoF, 3 GoF, 5 neutral).
• Null variants were associated with milder phenotypes (epilepsy, febrile seizures, rare DD/ID or psychiatric features).
• Missense LoF variants correlated with intermediate phenotypes (epilepsy, including DEEs, frequent DD/ID and psychiatric features).
• Gain-of-function (GoF) variants were linked to severe phenotypes, primarily DEEs with early onset and profound DD/ID.

Conclusions:

• The functional consequence of GABRG2 variants dictates disease severity.
• Null variants lead to mild phenotypes, missense LoF variants to intermediate phenotypes, and GoF variants to severe phenotypes.