Early onset or syndromic epilepsy

Gene: CLCN2

Comment on mode of inheritance: MOI has been changed from 'Both mono- and biallelic' to 'Monoallelic' only. Seizures have been linked with monoallelic variants (MIM# 607628) although there is debate regarding this gene-disease relationship, hence the current Red rating on this panel. Autosomal recessive pathogenic variants are also associated with Leukoencephalopathy (MIM# 615651) which does not include epilepsy.

Created: 15 Oct 2021, 1:55 p.m. | Last Modified: 15 Oct 2021, 1:55 p.m.

Panel Version: 2.447

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: Amber.

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

Panel Version: 1.189

I don't know

AD epilepsy - idiopathic generalised 11 (EIG11), juvenile absence 2 (EJA2), juvenille myoclonic 8 (EJM8). Sander et al, 2 sibs with juvenile absence epilepsy, Haug et al 2003 identified a het missense variant. Carried by another sib with generalised spike-wave discharges on EEG and dad reportedly had unclassified seizures in chldhood but has severe alcoholism so uncertain. Kleefus-Lie et al, 2009 - re-evaluated Sander and Haug which threw doubt on the Haug et al paper and Niemeyer et al 2010 said no evidence for a role of CLCN2 variants in idiopathic generalised epilepsy. Saint-Martin et al, 2009 - het mutation in 2 sibs of Tunisian origin not seen in a no of controls. Also 2 German sibs with idiopathic generalised epilepsy missense het variant diff to before. In both families unaff dad had mutation, therefore suggesting reduced penetrance/other factors required.

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, idiopathic generalized, susceptibility to, 11}, 607628; {Epilepsy, juvenile absence, susceptibility to, 2}, 607628; {Epilepsy, juvenile myoclonic, susceptibility to, 8}, 607628; Hyperaldosteronism, familial, type II, 605635; Leukoencephalopathy with ataxia, 615651

Red List (low evidence)

The association between CLCN2 and epilepsy has been refuted by ClinGen Epilepsy Expert Panel on the meeting date March 15, 2022 (https://search.clinicalgenome.org/kb/gene-validity/CGGV:assertion_ba2a1616-b3d7-4762-a546-c838333db683-2022-03-15T040000.000Z)

Created: 28 Nov 2023, 2:51 p.m. | Last Modified: 28 Nov 2023, 2:51 p.m.

Panel Version: 4.133

Controversy regarding association of CLCN2 variants, with PMID 20037607 refuting the report of CLCN2 variants in idiopathic generalized epilepsy in PMID 19710712

Created: 9 Apr 2018, 4:01 p.m.

Associated with phenotypes in OMIM, not in G2P. At least 2 heterozygous variants reported in two unrelated families with idiopathic generalized epilepsy (PMID 19191339)

Created: 6 Feb 2018, 10:21 a.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Leukoencephalopathy with ataxia, 615651; {Epilepsy, juvenile myoclonic, susceptibility to, 8}, 607628; {Epilepsy, juvenile absence, susceptibility to, 2}, 607628; {Epilepsy, idiopathic generalized, susceptibility to, 11}, 607628

Publications

• 23707145
• 19191339