Abstract
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.
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.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | 105236 |
| Tidsskrift | EBioMedicine |
| Vol/bind | 106 |
| Antal sider | 20 |
| ISSN | 2352-3964 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:This work was funded by the Australian National Health & Medical Research Council, the Novo Nordisk Foundation and The Lundbeck Foundation.The authors would like to thank the individuals and families who participated in our research studies. Furthermore, the authors would like to thank Dr Robin Cloarec for assisting with obtaining clinical phenotypic information. In addition, the authors would like to thank the Australian National Health & Medical Research Council grant APP1185122 (MC, NLA, PKA and RSM) and APP2019780 (PKA, MC, VWYL, and RSM), the Novo Nordisk Foundation NNF19OC0058749 (RSM) and The Lundbeck Foundation R383-2022-276 (RSM, PKA) for funding the project.
Funding Information:
The authors would like to thank the individuals and families who participated in our research studies. Furthermore, the authors would like to thank Dr Robin Cloarec for assisting with obtaining clinical phenotypic information. In addition, the authors would like to thank the Australian National Health & Medical Research Council grant APP1185122 (MC, NLA, PKA and RSM) and APP2019780 (PKA, MC, VWYL, and RSM), the Novo Nordisk Foundation NNF19OC0058749 (RSM) and The Lundbeck Foundation R383-2022-276 (RSM, PKA) for funding the project.
Publisher Copyright:
© 2024 The Authors