Distinct neurodevelopmental and epileptic phenotypes associated with gain- and loss-of-function GABRB2 variants

Area of Science:

• Neuroscience
• Genetics
• Molecular Biology

Background:

• GABRB2 gene variants are linked to a spectrum of neurological disorders, from febrile seizures to severe developmental and epileptic encephalopathies.
• The precise mechanisms differentiating milder from severe disease manifestations remain unclear.
• This study investigates genotype-phenotype correlations in individuals with GABRB2 variants.

Purpose of the Study:

• To conduct a comprehensive genotype-phenotype correlation analysis of GABRB2 variants.
• To elucidate the functional impact of GABRB2 variants on GABA receptor activity.
• To correlate specific variant functions (gain-of-function vs. loss-of-function) with distinct clinical phenotypes.

Main Methods:

• Collected genetic and electroclinical data from 42 individuals with 26 different GABRB2 variants.
• Performed electrophysiological analyses to assess the impact of variants on GABA receptor function.
• Correlated genotype data with clinical phenotypes, including developmental delay, movement disorders, and seizure types.

Main Results:

• 25 out of 26 GABRB2 variants impaired GABA receptor function, with 17 showing gain-of-function (GOF) and 8 showing loss-of-function (LOF).
• GOF variants were associated with severe developmental delay/intellectual disability (74%), movement disorders (59%), microcephaly (50%), and high early mortality (26%).
• LOF variants correlated with milder phenotypes, including fever-triggered seizures (92%), less severe DD/ID (85%), and preserved ambulatory function (85%).

Conclusions:

• GABRB2 variants exhibit divergent functional effects (GOF vs. LOF), directly correlating with distinct clinical outcomes.
• A diagnostic flowchart was developed to predict the pathogenicity of novel GABRB2 variants based on clinical presentation.
• This genotype-phenotype correlation provides a framework for understanding GABRB2-related disorders and aids in clinical diagnosis.