TY - JOUR
T1 - Distinct neurodevelopmental and epileptic phenotypes associated with gain- and loss-of-function GABRB2 variants
AU - Mohammadi, Nazanin Azarinejad
AU - Ahring, Philip Kiaer
AU - Liao, Vivian Wan Yu
AU - Chua, Han Chow
AU - Rosa, Sebastian Ortiz de la
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, Stephane
AU - Baer, Sarah
AU - Meyer, Pierre
AU - Milh, Mathieu
AU - Salpietro, Vincenzo
AU - Maroo, 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 - Moller, Rikke Steensbjerre
PY - 2024/8
Y1 - 2024/8
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.
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.
KW - Dystonia
KW - Epilepsy
KW - GABA A receptors
KW - Gain-of-function
KW - Movement disorders
KW - Seizures
KW - GABA receptors
UR - https://www.webofscience.com/api/gateway?GWVersion=2&SrcApp=web_of_science_starterapi&SrcAuth=WosAPI&KeyUT=WOS:001272920000001&DestLinkType=FullRecord&DestApp=WOS_CPL
UR - http://www.scopus.com/inward/record.url?scp=85197745491&partnerID=8YFLogxK
U2 - 10.1016/j.ebiom.2024.105236
DO - 10.1016/j.ebiom.2024.105236
M3 - Article
C2 - 38996765
SN - 2352-3964
VL - 106
JO - EBioMedicine
JF - EBioMedicine
M1 - 105236
ER -