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

Nathan L. Absalom, Vivian W. Y. Liao, Katrine M. H. Johannesen, Elena Gardella, Julia Jacobs, Gaetan Lesca, Zeynep Gokce-Samar, Alexis Arzimanoglou, Shimriet Zeidler, Pasquale Striano, Pierre Meyer, Ira Benkel-Herrenbrueck, Inger-Lise Mero, Jutta Rummel, Mary Chebib, Rikke S. Møller () and Philip K. Ahring ()
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Nathan L. Absalom: The University of Sydney
Vivian W. Y. Liao: The University of Sydney
Katrine M. H. Johannesen: The Danish Epilepsy Centre
Elena Gardella: The Danish Epilepsy Centre
Julia Jacobs: Medical Center-University of Freiburg
Gaetan Lesca: University Hospitals of Lyon (HCL)
Zeynep Gokce-Samar: University Hospitals of Lyon (HCL)
Alexis Arzimanoglou: University Hospitals of Lyon (HCL)
Shimriet Zeidler: Erasmus MC
Pasquale Striano: IRCCS Institute “Giannina Gaslini”
Pierre Meyer: Montpellier University Hospital
Ira Benkel-Herrenbrueck: Academic Teaching Hospital der Heinrich-Heine-University Düsseldorf
Inger-Lise Mero: Oslo University Hospital
Jutta Rummel: Oslo University Hospital
Mary Chebib: The University of Sydney
Rikke S. Møller: The Danish Epilepsy Centre
Philip K. Ahring: The University of Sydney

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Many patients with developmental and epileptic encephalopathies present with variants in genes coding for GABAA receptors. These variants are presumed to cause loss-of-function receptors leading to reduced neuronal GABAergic activity. Yet, patients with GABAA 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.

Date: 2022
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DOI: 10.1038/s41467-022-29280-x

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