Genetic Epilepsy

Gene: CLCN2

Red List (low evidence)

REFUTED classification by ClinGen - https://search.clinicalgenome.org/CCID:004463

Created: 18 Apr 2024, 10:56 p.m. | Last Modified: 18 Apr 2024, 10:56 p.m.

Panel Version: 0.2599

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
epilepsy (MONDO:0005027)

Publications

• https://search.clinicalgenome.org/CCID:004463

Red List (low evidence)

study of 32 patients with idiopathic generalised epilepsy, only did a panel of 18 genes. 2 patients iwth variants in CLCN2, both classified as VUS and both inherited but no information on phenotype of parents.

Created: 4 Dec 2023, 1:27 a.m. | Last Modified: 4 Dec 2023, 1:27 a.m.

Panel Version: 0.1950

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
Epilepsy susceptibility MIM#607628

Publications

• PMID: 36374051

Red List (low evidence)

Conflicting evidence regarding association with epilepsy syndromes, including one retracted paper.

In 3 of 46 unrelated families with IGE localized to 3q26, Haug et al. (2003) identified 3 mutations in the CLCN2 gene. In a re-evaluation of 2 of the families reported by Haug et al. (2003), Kleefuss-Lie et al. (2009) found discrepancies in the family structure, phenotype, and genetic analysis. On this basis, all but one of the original authors retracted the paper.

Stogmann et al. (2006) did not identify pathogenic mutations in the CLCN2 gene in 61 patients with IGE or 35 patients with temporal lobe epilepsy, suggesting that CLCN2 gene mutations are not a common cause of these disorders.

By sequencing of a large collection of human DNA followed by electrophysiologic analysis, Blanz et al. (2007) concluded that several CLCN2 sequence abnormalities previously found in patients with epilepsy most likely represented benign polymorphisms.

Saint-Martin et al. (2009) identified 2 different heterozygous variants in the CLCN2 gene in affected members of 2 unrelated families with juvenile myoclonic epilepsy (EJM8) and idiopathic generalized epilepsy (EIG11), respectively. In both families, the unaffected father also had the variant, suggesting either reduced penetrance or additional unidentified factors necessary for full phenotypic expression.

Niemeyer et al. (2010) disagreed with the conclusion by Kleefuss-Lie et al. (2009) that some of the work by Haug et al. (2003) had merit. Based on lack of functional consequences of the variants reported by Haug et al. (2003), Niemeyer et al. (2010) asserted that there is no evidence for a role of CLCN2 variants in idiopathic generalized epilepsy.
Sources: Expert Review

Created: 6 Oct 2021, 2:44 a.m.

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

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

Publications

• 23707145
• 19191339
• 20037607
• 19710712