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

Nazanin Azarinejad Mohammadi; Philip Kiær Ahring; Vivian Wan Yu Liao; Han Chow Chua; Sebastián Ortiz de la Rosa; Katrine Marie Johannesen; Yael Michaeli-Yossef; Aline Vincent-Devulder; Catherine Meridda; Ange-Line Bruel; Alessandra Rossi; Chirag Patel; Joerg Klepper; Paolo Bonanni; Sara Minghetti; Marina Trivisano; Nicola Specchio; David Amor; Stéphane Auvin; Sarah Baer; Pierre Meyer; Mathieu Milh; Vincenzo Salpietro; Reza Maroofian; Johannes R Lemke; Sarah Weckhuysen; Palle Christophersen; Guido Rubboli; Mary Chebib; Anders A Jensen; Nathan L Absalom; Rikke Steensbjerre Møller

doi:10.1016/j.ebiom.2024.105236

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

Nazanin Azarinejad Mohammadi, Philip Kiær Ahring, Vivian Wan Yu Liao, Han Chow Chua, Sebastián Ortiz de la Rosa, Katrine Marie Johannesen, Yael Michaeli-Yossef, Aline Vincent-Devulder, Catherine Meridda, Ange-Line Bruel, Alessandra Rossi, Chirag Patel, Joerg Klepper, Paolo Bonanni, Sara Minghetti, Marina Trivisano, Nicola Specchio, David Amor, Stéphane Auvin, Sarah BaerPierre Meyer, Mathieu Milh, Vincenzo Salpietro, Reza Maroofian, Johannes R Lemke, Sarah Weckhuysen, Palle Christophersen, Guido Rubboli, Mary Chebib, Anders A Jensen, Nathan L Absalom^*, Rikke Steensbjerre Møller^*

^*Corresponding author af dette arbejde

Filadelfia

Publikation: Bidrag til tidsskrift › Artikel › Forskning › peer review

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.

FUNDING: This work was funded by the Australian National Health & Medical Research Council, the Novo Nordisk Foundation and The Lundbeck Foundation.

Originalsprog	Engelsk
Artikelnummer	105236
Tidsskrift	EBioMedicine
Vol/bind	106
DOI	https://doi.org/10.1016/j.ebiom.2024.105236
Status	Udgivet - aug. 2024

Bibliografisk note

Adgang til dokumentet

10.1016/j.ebiom.2024.105236

Citationsformater

Mohammadi, N. A., Ahring, P. K., Yu Liao, V. W., Chua, H. C., Ortiz de la Rosa, S., Johannesen, K. M., Michaeli-Yossef, Y., Vincent-Devulder, A., Meridda, C., Bruel, A.-L., Rossi, A., Patel, C., Klepper, J., Bonanni, P., Minghetti, S., Trivisano, M., Specchio, N., Amor, D., Auvin, S., ... Møller, R. S. (2024). Distinct neurodevelopmental and epileptic phenotypes associated with gain- and loss-of-function GABRB2 variants. EBioMedicine, 106, Artikel 105236. https://doi.org/10.1016/j.ebiom.2024.105236

@article{dd2b462e72df493bb2a3a13a8aca73d0,

title = "Distinct neurodevelopmental and epileptic phenotypes associated with gain- and loss-of-function GABRB2 variants",

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.FUNDING: This work was funded by the Australian National Health & Medical Research Council, the Novo Nordisk Foundation and The Lundbeck Foundation.",

keywords = "Humans, Receptors, GABA-A/genetics, Male, Female, Phenotype, Genetic Association Studies, Epilepsy/genetics, Child, Child, Preschool, Gain of Function Mutation, Loss of Function Mutation, Neurodevelopmental Disorders/genetics, Genetic Predisposition to Disease, Adolescent, Infant, Adult, Genotype, Alleles",

author = "Mohammadi, {Nazanin Azarinejad} and Ahring, {Philip Ki{\ae}r} and {Yu Liao}, {Vivian Wan} and Chua, {Han Chow} and {Ortiz de la Rosa}, Sebasti{\'a}n and Johannesen, {Katrine Marie} and Yael Michaeli-Yossef and Aline Vincent-Devulder and Catherine Meridda and Ange-Line Bruel and Alessandra Rossi and Chirag Patel and Joerg Klepper and Paolo Bonanni and Sara Minghetti and Marina Trivisano and Nicola Specchio and David Amor and St{\'e}phane Auvin and Sarah Baer and Pierre Meyer and Mathieu Milh and Vincenzo Salpietro and Reza Maroofian and Lemke, {Johannes R} and Sarah Weckhuysen and Palle Christophersen and Guido Rubboli and Mary Chebib and Jensen, {Anders A} and Absalom, {Nathan L} and M{\o}ller, {Rikke Steensbjerre}",

year = "2024",

month = aug,

doi = "10.1016/j.ebiom.2024.105236",

language = "English",

volume = "106",

journal = "EBioMedicine",

issn = "2352-3964",

publisher = "Elsevier B.V.",

}

Mohammadi, NA, Ahring, PK, Yu Liao, VW, Chua, HC, Ortiz de la Rosa, S , Johannesen, KM, Michaeli-Yossef, Y, Vincent-Devulder, A, Meridda, C, Bruel, A-L, Rossi, A, Patel, C, Klepper, J, Bonanni, P, Minghetti, S, Trivisano, M, Specchio, N, Amor, D, Auvin, S, Baer, S, Meyer, P, Milh, M, Salpietro, V, Maroofian, R, Lemke, JR, Weckhuysen, S, Christophersen, P, Rubboli, G, Chebib, M, Jensen, AA, Absalom, NL & Møller, RS 2024, 'Distinct neurodevelopmental and epileptic phenotypes associated with gain- and loss-of-function GABRB2 variants', EBioMedicine, bind 106, 105236. https://doi.org/10.1016/j.ebiom.2024.105236

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

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.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 - Humans

KW - Receptors, GABA-A/genetics

KW - Male

KW - Female

KW - Phenotype

KW - Genetic Association Studies

KW - Epilepsy/genetics

KW - Child

KW - Child, Preschool

KW - Gain of Function Mutation

KW - Loss of Function Mutation

KW - Neurodevelopmental Disorders/genetics

KW - Genetic Predisposition to Disease

KW - Adolescent

KW - Infant

KW - Adult

KW - Genotype

KW - Alleles

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 -

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

Abstract

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