Article
Structural mapping of GABRB3 variants reveals genotype–phenotype correlations
Fecha
2021Registro en:
Johannesen KM, Iqbal S, Guazzi M, Mohammadi NA, Pérez-Palma E, Schaefer E, De Saint Martin A, Abiwarde MT, McTague A, Pons R, Piton A, Kurian MA, Ambegaonkar G, Firth H, Sanchis-Juan A, Deprez M, Jansen K, De Waele L, Briltra EH, Verbeek NE, van Kempen M, Fazeli W, Striano P, Zara F, Visser G, Braakman HMH, Haeusler M, Elbracht M, Vaher U, Smol T, Lemke JR, Platzer K, Kennedy J, Klein KM, Au PYB, Smyth K, Kaplan J, Thomas M, Dewenter MK, Dinopoulos A, Campbell AJ, Lal D, Lederer D, Liao VWY, Ahring PK, Møller RS, Gardella E. Structural mapping of GABRB3 variants reveals genotype-phenotype correlations. Genet Med. 2021 Dec 7:S1098-3600(21)05382-X. doi: 10.1016/j.gim.2021.11.004.
Autor
Johannesen, Katrine M.
Iqbal, Sumaiya
Guazzi, Milena
Mohammadi, Nazanin A.
Pérez Palma, Eduardo
Schaefer, Elise
San Martín, Ana de
Abiwarde, María Teresa
McTague, Amy
Pons, Roser
Pitón, Amélie
kuriano, Manju un
Ambegaonkar, Gautam
Fiordo, Helen
Sanchis-Juan, Alba
Deprez, Marie
Jansen, Katrien
Waele, Liesbeth De
Briltra, Eva H.
Verbeek, Nienke E.
Kempen, Marjan van
Fazeli, Walid
Striano, Pascual
Zara, Federico
Visser, Gerhard
Braakman, Hilde MH
Haeusler, Martin
Elbracht, Miriam
Vaher, Ulvi
Smol, Tomas
Lemke, Johannes R.
Platzer, Konrad
Kennedy, Joanna
Martín Klein, Carlos
Billie Au, Ping Yee
Smyth, Kimberly
Kaplan, Julie
Thomas, Morgan
Dewenter, Malin K.
Dinopoulos, Argirios
Campbell, Arturo J.
Lal, Dennis
Lederer, Damian
Liao, Vivian Wy
Ahring, Felipe K.
Møller, Rikke S.
Gardella, Elena
Institución
Resumen
Purpose
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
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Through an international collaboration, we analyzed electro-clinical data of unpublished individuals with variants in GABRB3, and we reviewed previously published cases.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.