Structural mapping of GABRB3 variants reveals genotype-phenotype correlations.
Genet Med
; 24(3): 681-693, 2022 03.
Article
in En
| MEDLINE
| ID: mdl-34906499
ABSTRACT
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 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Through an international collaboration, we analyzed electro-clinical data of unpublished individuals with variants in GABRB3, and we reviewed previously published cases.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.Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Epilepsy
/
Intellectual Disability
Limits:
Humans
Language:
En
Journal:
Genet Med
Journal subject:
GENETICA MEDICA
Year:
2022
Document type:
Article
Affiliation country:
Dinamarca