Early onset or syndromic epilepsy

Gene: SLC12A5

Green List (high evidence)

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

I don't know

Comment on mode of inheritance: Changed Mode of Inheritance from 'BOTH monoallelic and bialleic, autosomal or pseudoautosomal' to 'BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal' based on post-Webex review by Helen Lord.

Created: 7 Sep 2019, 11:50 a.m. | Last Modified: 7 Sep 2019, 11:50 a.m.

Panel Version: 1.288

Mode of inheritance collated by Helen Lord (Oxford University Hospitals NHS Foundation Trust, 2019_08_30) on behalf of West Midlands, Oxford and Wessex GLH for GMS Neurology specialist test group. This gene is part of a subset where the mode of inheritance was re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy. No rating was included in the review, so I have uploaded a Green rating to match the original West Midlands, Oxford and Wessex GLH rating.

Created: 5 Sep 2019, 2:26 p.m. | Last Modified: 5 Sep 2019, 2:26 p.m.

Panel Version: 1.262

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: Green.

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

Panel Version: 1.189

Green List (high evidence)

AR EIEE34 & AD generalised idiopathic epilepsy 14. AR EIEE34 - Stodberg et al, 2015 - 4 children from 2 unrelated families - hom/compound het variants in these families - in vitro studies showed that the nutations caused decreased membrane expression, impaired posttrnslational modification and a loss of transporter function resulting in impaired normal synaptic inhibition and promition if neuronal excitability. AD epilepsy - Kahle et al, 2014 - 380 epilepsy patients - 8 patients of French Canadian origin had two diff missense variants (5 - R952H & 3 - R1049C). In vitro expression studies showed that the variants impaired the functon of SLC12A5. Puskarjov et al, 2014 - 3 aff family members in an Australian family - R952H. In vitro studies also done - support pathogenicity.

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

Panel Version: 1.188

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Epileptic encephalopathy, early infantile, 616645; {Epilepsy, idiopathic generalized, susceptibility to}; 616685

Publications

• 26333769
• 27436767

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• Stodberg et al (2015) Nat. Commun. 6:8038 doi: 10.1038/ncomms9038

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• Stodberg et al (2015) Nat. Commun. 6:8038 doi: 10.1038/ncomms9038

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• Stodberg et al (2015) Nat. Commun. 6:8038 doi: 10.1038/ncomms9038

Variants in this GENE are reported as part of current diagnostic practice

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• Stodberg et al (2015) Nat. Commun. 6:8038 doi: 10.1038/ncomms9038

Variants in this GENE are reported as part of current diagnostic practice

Comment on mode of inheritance: Both applies to information from reviewers, G2P and OMIM, and publications.

Created: 29 Jan 2016, 5:10 p.m.

PMID: 25839329 - Two families, each with two children with EIMFS with similar presentation, were investigated. Missense mutations within the SLC12A5 gene were reported in all four children, with a recessive mode of inheritance. The children from Family A were compound heterozygotes for missense mutations c.1277T>C (L426P) and c.1652G>A (G551D). The affected patients from Family B were homozygous for the missense variant c.932T>A (L311H). Parents were heterozygous carriers. No potential pathogenic variants were found in known EIMFS or EIEE genes in the families. Postulated mechanism from in vitro/in vivo studies is through reduced surface expression, impairing normal synaptic inhibition and promoting neuronal excitability.

PMID: 24668262 - 378 patients with seizure disorders were analyzed and 11 rare variants in SLC12A% were identified. In one family, rs142740233 NM_020708.4:c.2855G>A missense variant (causing Arg>His at position 952 in KCC2b and 975 in KCC2a) was found. The KCC2b isoform of the variant (named KCC2-R952H) was investigated further and was shown to result in reduced cell surface expression.

Created: 21 Jan 2016, 1:51 p.m.

Comment on phenotypes: From PMID: 26333769

Created: 21 Jan 2016, 1:12 p.m.