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Intellectual disability

Gene: GABRD

Amber List (moderate evidence)

GABRD (gamma-aminobutyric acid type A receptor delta subunit)
EnsemblGeneIds (GRCh38): ENSG00000187730
EnsemblGeneIds (GRCh37): ENSG00000187730
OMIM: 137163, Gene2Phenotype
GABRD is in 2 panels

1 review

Arina Puzriakova (Genomics England Curator)

Green List (high evidence)

Comment on list classification: There are sufficient unrelated cases to rate this gene as Green at the next GMS panel update. Although all patients presented epilepsy, it is not clear from the case reports whether cognitive impairment was secondary or independent of seizures. For this reason I think its worth including GABRD on this panel as it is plausible that DD may be evident prior to seizure onset (ranging from 4 months to 4 years in report)
Created: 17 Nov 2021, 3:11 p.m. | Last Modified: 17 Nov 2021, 3:11 p.m.
Panel Version: 3.1458
Ahring et al., 2021 (PMID: 34633442) reports on at least 3 unrelated individuals with de novo variants and one family with 3 affected individuals harbouring an inherited variant in the GABRD gene. All variants exerted a gain-of-function effect and all carriers displayed a homogenous phenotype of generalised epilepsy (median age of onset 10.5 months, medically refractory in 5/6) and various degrees of learning difficulties or ID (learning difficulties in 1, mild ID in 2, mild to moderate ID in 1, and severe to profound ID in 2).

NB. A further three individuals were excluded from phenotypic analysis as their variants (p.M87L and p.V442I) did not show any detectable functional changes. There was also another patient with a loss-of-function variant but they displayed ASD, normal intelligence and no seizure history.
Sources: Literature
Created: 17 Nov 2021, 3:02 p.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
{Epilepsy, idiopathic generalized, 10}, OMIM:613060; {Epilepsy, juvenile myoclonic, susceptibility to}, OMIM:613060

Publications

Mode of pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments

Details

Mode of Inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Sources
  • Expert Review Amber
  • Literature
Phenotypes
  • {Epilepsy, idiopathic generalized, 10}, OMIM:613060
  • {Epilepsy, juvenile myoclonic, susceptibility to}, OMIM:613060
Tags
Q4_21_rating
OMIM
137163
Clinvar variants
Variants in GABRD
Penetrance
None
Publications
Mode of Pathogenicity
Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments
Panels with this gene

History Filter Activity

17 Nov 2021, Gel status: 2

Entity classified by Genomics England curator

Arina Puzriakova (Genomics England Curator)

Gene: gabrd has been classified as Amber List (Moderate Evidence).

17 Nov 2021, Gel status: 1

Created, Added New Source, Added Tag, Set mode of inheritance, Set publications, Set Phenotypes, Set mode of pathogenicity

Arina Puzriakova (Genomics England Curator)

gene: GABRD was added gene: GABRD was added to Intellectual disability. Sources: Literature Q4_21_rating tags were added to gene: GABRD. Mode of inheritance for gene: GABRD was set to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted Publications for gene: GABRD were set to 34633442 Phenotypes for gene: GABRD were set to {Epilepsy, idiopathic generalized, 10}, OMIM:613060; {Epilepsy, juvenile myoclonic, susceptibility to}, OMIM:613060 Mode of pathogenicity for gene: GABRD was set to Loss-of-function variants (as defined in pop up message) DO NOT cause this phenotype - please provide details in the comments Review for gene: GABRD was set to GREEN