Gain-of-function and loss-of-function GABRB3 variants lead to distinct clinical phenotypes in patients with developmental and epileptic encephalopathies

Genetic variants of gamma-aminobutyric acid (GABA(A)) receptors are associated with early onset epilepsies. Here, the authors show that functional loss or gain-of-function defines clinical outcomes, with gain-of-function variants unexpectedly more severe. Many patients with developmental and epileptic encephalopathies present with variants in genes coding for GABA(A) receptors. These variants are presumed to cause loss-of-function receptors leading to reduced neuronal GABAergic activity. Yet, patients with GABA(A) receptor variants have diverse clinical phenotypes and many are refractory to treatment despite the availability of drugs that enhance GABAergic activity. Here we show that 44 pathogenic GABRB3 missense variants segregate into gain-of-function and loss-of-function groups and respective patients display distinct clinical phenotypes. The gain-of-function cohort (n = 27 patients) presented with a younger age of seizure onset, higher risk of severe intellectual disability, focal seizures at onset, hypotonia, and lower likelihood of seizure freedom in response to treatment. Febrile seizures at onset are exclusive to the loss-of-function cohort (n = 47 patients). Overall, patients with GABRB3 variants that increase GABAergic activity have more severe developmental and epileptic encephalopathies. This paradoxical finding challenges our current understanding of the GABAergic system in epilepsy and how patients should be treated.

Automated summary

This study discovered that pathogenic mutations in the GABRB3 gene can be divided into gain-of-function and loss-of-function groups, with patients in each group displaying distinct clinical features. Patients with gain-of-function mutations had earlier age of seizure onset, higher risk of severe intellectual disability, more severe seizures, and poorer response to treatment. Febrile seizures at onset were exclusively found in patients with loss-of-function mutations.