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Structural mapping of GABRB3 variants reveals genotype-phenotype correlations

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dc.contributor.authorJohannesen, Katrine
dc.contributor.authorIqba, Sumaiya
dc.contributor.authorGuazz, Milena
dc.contributor.authorMohammadi, Nazanin
dc.contributor.authorPérez, Eduardo
dc.contributor.authorSchaefer, Elise
dc.contributor.authorDe Saint Martin, Anne
dc.contributor.authorAbiwarde, Marie
dc.contributor.authorMcTague, Amy
dc.contributor.authorPons, Roser
dc.contributor.authorPiton, Amelie
dc.contributor.authorKurian, Manju
dc.contributor.authorAmbegaonkar, Gautam
dc.contributor.authorFirth, Helen
dc.contributor.authorSanchis, Alba
dc.contributor.authorDeprez, Marie
dc.contributor.authorJansen, Katrien
dc.contributor.authorDe Waele, Liesbeth
dc.contributor.authorBriltra, Eva
dc.contributor.authorVerbeek, Nienke
dc.contributor.authorVan Kempen, Marjan
dc.contributor.authorFazeli, Walid
dc.contributor.authorStriano, Pasquale
dc.contributor.authorZara, Federico
dc.contributor.authorVisser, Gerhard
dc.contributor.authorBraakman, Hilde
dc.contributor.authorHaeusle, Martin
dc.contributor.authorElbracht, Miriam
dc.contributor.authorVahe, Ulvi
dc.contributor.authorSmol, Thomas
dc.contributor.authorLemke, Johannes
dc.contributor.authorPlatzer, Konrad
dc.contributor.authorKennedy, Joanna
dc.contributor.authorMartin, Karl
dc.contributor.authorPing, Billie
dc.contributor.authorSmyth, Kimberly
dc.contributor.authorKaplan, Julie
dc.contributor.authorThomas, Morgan
dc.contributor.authorDewenter, Malin
dc.contributor.authorDinopoulos, Argirios
dc.contributor.authorCampbell, Arthur
dc.contributor.authorLal, Dennis
dc.contributor.authorLederer, Damien
dc.contributor.authorLiao, Vivian
dc.contributor.authorAhring, Philip
dc.contributor.authorMøller, Rikke
dc.contributor.authorGardella, Elena
dc.date.accessioned2023-03-31T18:04:26Z
dc.date.available2023-03-31T18:04:26Z
dc.date.issued2021
dc.description.abstractPurpose: Pathogenic variants in GABRB3 have been associated with a spectrum of phenotypes from severe developmental disorders and epileptic encephalopathies to milder epilepsy syndromes and mild intellectual disability (ID). In this study, we analyzed a large cohort of individuals with GABRB3 variants to deepen the phenotypic understanding and investigate genotype-phenotype correlations. Methods: Through an international collaboration, we analyzed electro-clinical data of unpublished individuals with variants in GABRB3, and we reviewed previously published cases. All missense variants were mapped onto the 3-dimensional structure of the GABRB3 subunit, and clinical phenotypes associated with the different key structural domains were investigated. Results: We characterized 71 individuals with GABRB3 variants, including 22 novel subjects, expressing a wide spectrum of phenotypes. Interestingly, phenotypes correlated with structural locations of the variants. Generalized epilepsy, with a median age at onset of 12 months, and mild-to-moderate ID were associated with variants in the extracellular domain. Focal epilepsy with earlier onset (median: age 4 months) and severe ID were associated with variants in both the pore-lining helical transmembrane domain and the extracellular domain. Conclusion: These genotype-phenotype correlations will aid the genetic counseling and treatment of individuals affected by GABRB3-related disorders. Future studies may reveal whether functional differences underlie the phenotypic differences.
dc.description.versionVersión publicada
dc.identifier.doihttps://doi.org/10.1016/j.gim.2021.11.004
dc.identifier.urihttps://repositorio.udd.cl/handle/11447/7226
dc.language.isoen
dc.subjectEpilepsy
dc.subjectGABA
dc.subjectGABRB3
dc.subjectGenetics
dc.subjectMapping
dc.titleStructural mapping of GABRB3 variants reveals genotype-phenotype correlations
dc.typeArticle
dcterms.accessRightsAcceso abierto
dcterms.sourceGenetics in medicine : official journal of the American College of Medical Genetics
dspace.entity.typePublication

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