Early onset or syndromic epilepsy
Gene: CLCN2Comment 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
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
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
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 19710712Created: 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
Phenotypes for gene: CLCN2 were changed from 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 to {Epilepsy, juvenile myoclonic, susceptibility to, 8}, OMIM:607628; {Epilepsy, juvenile absence, susceptibility to, 2}, OMIM:607628; {Epilepsy, idiopathic generalized, susceptibility to, 11}, OMIM:607628
Mode of inheritance for gene: CLCN2 was changed from BOTH monoallelic and biallelic, autosomal or pseudoautosomal to MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted
Source Wessex and West Midlands GLH was added to CLCN2.
Source NHS GMS was added to CLCN2.
Sarah Leigh: Associated with phenotypes in
Gene: clcn2 has been classified as Red List (Low Evidence).
NIHRBR-RD Consortium SPEED_v3.0_20170404 was added to CLCN2. Panel: Genetic Epilepsy Syndromes
Publications for CLCN2 were set to 23707145; 19191339; 20037607; 19710712
CLCN2 was added to Genetic Epilepsy Syndromes panel. Sources: Literature
CLCN2 was created by Sarah Leigh