Early onset or syndromic epilepsy

Gene: GABRD

Comment on list classification: Upgraded from Red to Amber but this gene should now be promoted to Green at the next GMS panel update.

New evidence identified by Helen Lord (OUH NHS) highlights at least 3 unrelated individuals with de novo variants and one family with 3 affected individuals harbouring an inherited variant in the GABRD gene (PMID: 34633442). 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.

Created: 17 Nov 2021, 2:13 p.m. | Last Modified: 17 Nov 2021, 2:13 p.m.

Panel Version: 2.470

Green List (high evidence)

Screened the GABRD gene in a cohort of 933 individuals with various childhood-onset epilepsies sequentially referred for diagnostic gene panel testing. The genetic findings were obtained either through targeted epilpesy panels (n=4), WES (n=3) or sanger sequencing (n=3; family 1 patient 6 & 7, family 2 patient 10). Variants classified using the ACMG criteria and badsed on transcript NM_000815.4.
From the original cohort of 933 individuals, presumed pathogenic variants were identified in 3 individuals from 2 unrelated families. Another 7 individuals from 6 families with epilepsy or neurodevelopmental disorders were identified through international collaberations and gene matcher.
The V422I variant occured presumably de novo in two sibs thus one parent must be mosaic.
The T291I variant was detected in an aff mother and her aff twin boys.
The remaining variants M87L, P122A, P257L, L260V & I284T all occured de novo in sporadic patients.
All 7 variants were predicted to be damaging by at least two different prediction tools and had CADD scores above 20. 6 of 7 were absent in gnomAD and our internal dataset. The M87L variant was seen once in gnomAD.
The position of the different variants spans a large part of the delta subunit from the N-terminal end (M87L) to the final transmembrane M4 domain (V442I). Four of the variants (P257L, L260V, I284T & T291I) reside in the M1 and M2 transmembrane domains that are key to forming a functional ion channel. 5 of the 7 variants cause changes to AA residues fully (P122A, P257L & T291I) or highly (L260V & I284T) conserved across human GABAaR subunits.
Functional analysis suggests:
P122A variant results in a 5-fold decrease in the average maximal current amplitude and combined with its increaesed propensity to desensitise - LOF trait.
The 4 variants in the transmembrane domains M1 & M2 (P257L, L260V, I284T, T291I) all resulted in a 3-18 fold increased in current amplitudes - GOF trait.The current amplitude increase in P257L was only 3 fold and this receptor also displayed increased sensitivty to GABA reinforcing the GOF trait.
No functional changes noted for M87L and V422I. As these variants haven't shown any detectable functional changes the 3 individuals carrying these two changes are not included in the phenotypic analysis.

The remaining 7 patients median age of 10 years (ranging from 3-37)/All 6 patients with a GOF variant suffered from generalised epilesy (nost common seizure types atypical absences, generalised myoclonic seizures, tonic seizures and generalised tonic-clonic seizures; occur daily in 4/6 patients and medically refractory in 5/6 patients)and various degrees of learning difficuties or intellectual disability (motor delay in 4/6 with regression or stagnation at seizure onset in at least 2, learning difficulties seen in 6/6 from mild to severe), EEG pattern suggests an underlying cortico-thalmic network tyocial for generalised epilepsys with diffuse spiked and slow waves shown in both humans and animal models~).
The patient with the LOF variant has ASD, normal intelligence and no seizure history.

In summary presumed pathogenic LOF variants were identified in 3 individuals (de novo) and one family (2 twin sibs and mother all aff) with an epilepsy and neurodev disorder.
One GOF variant was identifed (de novo) in a patient with ASD but no seizures.
Two other variants identified in this gene in patients with seizure phenotypes were excluded from phentoypic interpretation as the functional analysis undertaken showed no effect - unclear as to whether these are pathogenic or not.

Created: 1 Nov 2021, 10:24 a.m. | Last Modified: 1 Nov 2021, 10:24 a.m.

Panel Version: 2.452

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Neurodevelopmental disorders; generalised epilepsy

Publications

• 34633442

I don't know

Review and rating collated by Tracy Lester (Oxford Medical Genetics Laboratories Oxford University Hospitals NHS Foundation Trust, 2019_02_06) on behalf of Wessex and West Midlands GLH for GMS Neurology specialist test group, for Clinical Indication R59 'Early onset or syndromic epilepsy'. Review contributors: John Taylor and Helen Lord. Suggested gene rating: Red.

Created: 6 Aug 2019, 8:38 p.m. | Last Modified: 6 Aug 2019, 8:38 p.m.

Panel Version: 1.189

Red List (low evidence)

AD Epilepsy - paper by Dibbens et al 2004 one individual hom for R220H variant - daughter het. Lenzen et al 2005 disagreed with the findings.

Created: 6 Aug 2019, 8:31 p.m. | Last Modified: 6 Aug 2019, 8:31 p.m.

Panel Version: 1.188

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
{Epilepsy, generalized, with febrile seizures plus, type 5, susceptibility to}, 613060 ; {Epilepsy, idiopathic generalized, 10}, 613060 ; {Epilepsy, juvenile myoclonic, susceptibility to}, 613060

Publications

• 15115768

Red List (low evidence)

Publications

• 15115768

The rating of this gene has been updated followingNHS Genomic Medicine Serviceapproval.

Created: 11 Mar 2022, 3:31 p.m. | Last Modified: 11 Mar 2022, 3:31 p.m.

Panel Version: 2.498

Comment on list classification: Associated with phenotype in OMIM and not in Gen2Phen. At least 2 variants identified in unrelated cases. The variant are associated with susceptibility to the phenotypes and c.659G>A polymorphism may also increase the duration of postictal period in Juvenile myoclonic epilepsy patients but may decrease the duration of seizure in Lennox-Gastaut syndrome patients (PMID 29785705).

Created: 21 Jun 2018, 10:16 a.m.

Red List (low evidence)

Red List (low evidence)

Red List (low evidence)

Red List (low evidence)