TY - JOUR

T1 - Distinct neurodevelopmental and epileptic phenotypes associated with gain- and loss-of-function GABRB2 variants

AU - Mohammadi, Nazanin Azarinejad

AU - Ahring, Philip Kiær

AU - Yu Liao, Vivian Wan

AU - Chua, Han Chow

AU - Ortiz de la Rosa, Sebastián

AU - Johannesen, Katrine Marie

AU - Michaeli-Yossef, Yael

AU - Vincent-Devulder, Aline

AU - Meridda, Catherine

AU - Bruel, Ange Line

AU - Rossi, Alessandra

AU - Patel, Chirag

AU - Klepper, Joerg

AU - Bonanni, Paolo

AU - Minghetti, Sara

AU - Trivisano, Marina

AU - Specchio, Nicola

AU - Amor, David

AU - Auvin, Stéphane

AU - Baer, Sarah

AU - Meyer, Pierre

AU - Milh, Mathieu

AU - Salpietro, Vincenzo

AU - Maroofian, Reza

AU - Lemke, Johannes R.

AU - Weckhuysen, Sarah

AU - Christophersen, Palle

AU - Rubboli, Guido

AU - Chebib, Mary

AU - Jensen, Anders A.

AU - Absalom, Nathan L.

AU - Møller, Rikke Steensbjerre

N1 - Publisher Copyright: © 2024 The Authors

PY - 2024

Y1 - 2024

N2 - Background: Variants in GABRB2, encoding the β2 subunit of the γ-aminobutyric acid type A (GABAA) receptor, can result in a diverse range of conditions, ranging from febrile seizures to severe developmental and epileptic encephalopathies. However, the mechanisms underlying the risk of developing milder vs more severe forms of disorder remain unclear. In this study, we conducted a comprehensive genotype–phenotype correlation analysis in a cohort of individuals with GABRB2 variants. Methods: Genetic and electroclinical data of 42 individuals harbouring 26 different GABRB2 variants were collected and accompanied by electrophysiological analysis of the effects of the variants on receptor function. Findings: Electrophysiological assessments of α1β2γ2 receptors revealed that 25/26 variants caused dysfunction to core receptor properties such as GABA sensitivity. Of these, 17 resulted in gain-of-function (GOF) while eight yielded loss-of-function traits (LOF). Genotype-phenotype correlation analysis revealed that individuals harbouring GOF variants suffered from severe developmental delay/intellectual disability (DD/ID, 74%), movement disorders such as dystonia or dyskinesia (59%), microcephaly (50%) and high risk of early mortality (26%). Conversely, LOF variants were associated with milder disease manifestations. Individuals with these variants typically exhibited fever-triggered seizures (92%), milder degrees of DD/ID (85%), and maintained ambulatory function (85%). Notably, severe movement disorders or microcephaly were not reported in individuals with loss-of-function variants. Interpretation: The data reveals that genetic variants in GABRB2 can lead to both gain and loss-of-function, and this divergence is correlated with distinct disease manifestations. Utilising this information, we constructed a diagnostic flowchart that aids in predicting the pathogenicity of recently identified variants by considering clinical phenotypes. Funding: This work was funded by the Australian National Health & Medical Research Council, the Novo Nordisk Foundation and The Lundbeck Foundation.

AB - Background: Variants in GABRB2, encoding the β2 subunit of the γ-aminobutyric acid type A (GABAA) receptor, can result in a diverse range of conditions, ranging from febrile seizures to severe developmental and epileptic encephalopathies. However, the mechanisms underlying the risk of developing milder vs more severe forms of disorder remain unclear. In this study, we conducted a comprehensive genotype–phenotype correlation analysis in a cohort of individuals with GABRB2 variants. Methods: Genetic and electroclinical data of 42 individuals harbouring 26 different GABRB2 variants were collected and accompanied by electrophysiological analysis of the effects of the variants on receptor function. Findings: Electrophysiological assessments of α1β2γ2 receptors revealed that 25/26 variants caused dysfunction to core receptor properties such as GABA sensitivity. Of these, 17 resulted in gain-of-function (GOF) while eight yielded loss-of-function traits (LOF). Genotype-phenotype correlation analysis revealed that individuals harbouring GOF variants suffered from severe developmental delay/intellectual disability (DD/ID, 74%), movement disorders such as dystonia or dyskinesia (59%), microcephaly (50%) and high risk of early mortality (26%). Conversely, LOF variants were associated with milder disease manifestations. Individuals with these variants typically exhibited fever-triggered seizures (92%), milder degrees of DD/ID (85%), and maintained ambulatory function (85%). Notably, severe movement disorders or microcephaly were not reported in individuals with loss-of-function variants. Interpretation: The data reveals that genetic variants in GABRB2 can lead to both gain and loss-of-function, and this divergence is correlated with distinct disease manifestations. Utilising this information, we constructed a diagnostic flowchart that aids in predicting the pathogenicity of recently identified variants by considering clinical phenotypes. Funding: This work was funded by the Australian National Health & Medical Research Council, the Novo Nordisk Foundation and The Lundbeck Foundation.

KW - Dystonia

KW - Epilepsy

KW - GABA receptors

KW - Gain-of-function

KW - Movement disorders

KW - Seizures

U2 - 10.1016/j.ebiom.2024.105236

DO - 10.1016/j.ebiom.2024.105236

M3 - Journal article

C2 - 38996765

AN - SCOPUS:85197745491

VL - 106

JO - EBioMedicine

JF - EBioMedicine

SN - 2352-3964

M1 - 105236

ER -