GABRA1-related disorders: from genetic to functional pathways
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GABRA1-related disorders : from genetic to functional pathways. / Musto, Elisa; Liao, Vivian W Y; Johannesen, Katrine M; Fenger, Christina D; Lederer, Damien; Kothur, Kavitha; Fisk, Katrina; Bennetts, Bruce; Vrielynck, Pascal; Delaby, Delphine; Ceulemans, Berten; Weckhuysen, Sarah; Sparber, Peter; Bouman, Arjan; Ardern-Holmes, Simone; Troedson, Christopher; Battaglia, Domenica I; Goel, Himanshu; Feyma, Timothy; Bakhtiari, Somayeh; Tjoa, Linda; Boxill, Martin; Demina, Nina; Shchagina, Olga; Dadali, Elena; Kruer, Michael; Cantalupo, Gaetano; Contaldo, Ilaria; Polster, Tilman; Isidor, Bertrand; Bova, Stefania M; Fazeli, Walid; Wouters, Leen; Miranda, Maria J; Darra, Francesca; Pede, Elisa; Le Duc, Diana; Jamra, Rami Abou; Küry, Sébastien; Proietti, Jacopo; McSweeney, Niamh; Brokamp, Elly; Andrews, Peter Ian; Gouray Garcia, Marie; Chebib, Mary; Møller, Rikke S; Ahring, Philip K; Gardella, Elena.
In: Annals of Neurology, Vol. 95, No. 1, 2024, p. 27-41.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - GABRA1-related disorders
T2 - from genetic to functional pathways
AU - Musto, Elisa
AU - Liao, Vivian W Y
AU - Johannesen, Katrine M
AU - Fenger, Christina D
AU - Lederer, Damien
AU - Kothur, Kavitha
AU - Fisk, Katrina
AU - Bennetts, Bruce
AU - Vrielynck, Pascal
AU - Delaby, Delphine
AU - Ceulemans, Berten
AU - Weckhuysen, Sarah
AU - Sparber, Peter
AU - Bouman, Arjan
AU - Ardern-Holmes, Simone
AU - Troedson, Christopher
AU - Battaglia, Domenica I
AU - Goel, Himanshu
AU - Feyma, Timothy
AU - Bakhtiari, Somayeh
AU - Tjoa, Linda
AU - Boxill, Martin
AU - Demina, Nina
AU - Shchagina, Olga
AU - Dadali, Elena
AU - Kruer, Michael
AU - Cantalupo, Gaetano
AU - Contaldo, Ilaria
AU - Polster, Tilman
AU - Isidor, Bertrand
AU - Bova, Stefania M
AU - Fazeli, Walid
AU - Wouters, Leen
AU - Miranda, Maria J
AU - Darra, Francesca
AU - Pede, Elisa
AU - Le Duc, Diana
AU - Jamra, Rami Abou
AU - Küry, Sébastien
AU - Proietti, Jacopo
AU - McSweeney, Niamh
AU - Brokamp, Elly
AU - Andrews, Peter Ian
AU - Gouray Garcia, Marie
AU - Chebib, Mary
AU - Møller, Rikke S
AU - Ahring, Philip K
AU - Gardella, Elena
N1 - This article is protected by copyright. All rights reserved.
PY - 2024
Y1 - 2024
N2 - OBJECTIVE: Variants in GABRA1 have been associated with a broad epilepsy spectrum, ranging from genetic generalized epilepsies to developmental and epileptic encephalopathies. However, our understanding of what determines the phenotype severity and best treatment options remains inadequate. We therefore aimed to analyse the electro-clinical features and the functional effects of GABRA1-variants to establish genotype-phenotype correlations.METHODS: Genetic and electro-clinical data of 27 individuals (22 unrelated and 2 families) harbouring 20 different GABRA1 variants were collected and accompanied with functional analysis of 19 variants.RESULTS: Individuals in this cohort could be assigned into different clinical subgroups based on the functional effect of their variant and its structural position within the GABRA1 subunit. A homogenous phenotype with mild cognitive impairment and infantile-onset epilepsy (focal seizures, fever sensitivity and EEG posterior epileptiform discharges) was described for variants in the extra-cellular domain and the small transmembrane loops. These variants displayed loss-of-function (LoF) effects and the patients generally had a favourable outcome. A more severe phenotype was associated with variants in the pore-forming transmembrane helices. These variants displayed either gain-of-function (GoF) or LoF effects. GoF-variants were associated with severe early-onset neurodevelopmental disorders, including early infantile developmental and epileptic encephalopathy.INTERPRETATION: Our data expand the genetic and phenotypic spectrum of GABRA1-epilepsies and permit to delineate specific sub-phenotypes for LoF and GoF variants, though the heterogeneity of phenotypes and variants. Generally, variants in the transmembrane helices cause more severe phenotypes, in particular GoF variants. These findings establish the basis for a better understanding of the patho-mechanism and precision medicine approach in GABRA1-related disorders. Further studies in larger populations are needed to provide a conclusive genotype-phenotype correlation. This article is protected by copyright. All rights reserved.
AB - OBJECTIVE: Variants in GABRA1 have been associated with a broad epilepsy spectrum, ranging from genetic generalized epilepsies to developmental and epileptic encephalopathies. However, our understanding of what determines the phenotype severity and best treatment options remains inadequate. We therefore aimed to analyse the electro-clinical features and the functional effects of GABRA1-variants to establish genotype-phenotype correlations.METHODS: Genetic and electro-clinical data of 27 individuals (22 unrelated and 2 families) harbouring 20 different GABRA1 variants were collected and accompanied with functional analysis of 19 variants.RESULTS: Individuals in this cohort could be assigned into different clinical subgroups based on the functional effect of their variant and its structural position within the GABRA1 subunit. A homogenous phenotype with mild cognitive impairment and infantile-onset epilepsy (focal seizures, fever sensitivity and EEG posterior epileptiform discharges) was described for variants in the extra-cellular domain and the small transmembrane loops. These variants displayed loss-of-function (LoF) effects and the patients generally had a favourable outcome. A more severe phenotype was associated with variants in the pore-forming transmembrane helices. These variants displayed either gain-of-function (GoF) or LoF effects. GoF-variants were associated with severe early-onset neurodevelopmental disorders, including early infantile developmental and epileptic encephalopathy.INTERPRETATION: Our data expand the genetic and phenotypic spectrum of GABRA1-epilepsies and permit to delineate specific sub-phenotypes for LoF and GoF variants, though the heterogeneity of phenotypes and variants. Generally, variants in the transmembrane helices cause more severe phenotypes, in particular GoF variants. These findings establish the basis for a better understanding of the patho-mechanism and precision medicine approach in GABRA1-related disorders. Further studies in larger populations are needed to provide a conclusive genotype-phenotype correlation. This article is protected by copyright. All rights reserved.
U2 - 10.1002/ana.26774
DO - 10.1002/ana.26774
M3 - Journal article
C2 - 37606373
VL - 95
SP - 27
EP - 41
JO - Annals of Neurology
JF - Annals of Neurology
SN - 0364-5134
IS - 1
ER -
ID: 368136014