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

Nathan Absalom (1, 2) , Vivian Liao (1) , Katrine Johannesen (3, 4) , Elena Gardella (3, 4) , Julia Jacobs (5, 6) , Gaetan Lesca (7, 8) , Zeynep Gokce-Samar (8) , Alexis Arzimanoglou (8) , Shimriet Zeidler (9) , Pasquale Striano (10, 11) , Pierre Meyer (12, 13) , Ira Benkel-Herrenbrueck (14) , Inger-Lise Mero (15) , Jutta Rummel (15) , Mary Chebib (1) , Rikke Møller (3, 4) , Philip Ahring (1)

1 The University of Sydney
2 Western Sydney University
3 The Danish Epilepsy Centre Filadelfia [Dianalund, Denmark]
4 SDU - University of Southern Denmark
5 University of Calgary
6 University of Freiburg [Freiburg]
7 INMG - Institut NeuroMyoGène
8 HCL - Hospices Civils de Lyon
9 Erasmus MC - Erasmus University Medical Center [Rotterdam]
10 IRCCS Istituto Giannina Gaslini [Genoa, Italy]
11 UniGe - Università degli studi di Genova = University of Genoa
12 PhyMedExp - Physiologie & médecine expérimentale du Cœur et des Muscles [U 1046]
13 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
14 Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf]
15 Oslo University Hospital [Oslo]

Abstract 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.

Domaines: Sciences du Vivant [q-bio]

Nathan Absalom, Vivian Liao, Katrine Johannesen, Elena Gardella, Julia Jacobs, et al.. Gain-of-function and loss-of-function GABRB3 variants lead to distinct clinical phenotypes in patients with developmental and epileptic encephalopathies. Nature Communications, 2022, 13 (1), pp.1822. ⟨10.1038/s41467-022-29280-x⟩. ⟨hal-03633628⟩