Early onset or syndromic epilepsy

Gene: SLC25A12

Green List (high evidence)

AR EIEE39 on OMIM. Wibom et al 2009 (19641205) - swedish girl found to have a hom SLC25A12 variant and functional expression studies showed impaired protein activity. Falk et al 2014 (24515575) - 2 sibs of consang Indian parents - hom missense variant - in vitro functional expression studes in E Coli showed that the mutant protein had about 15% residual activity. Pronicka et al, 2016 (27290639) - hom novel missense variant detected - patient 24 in the supp info - had epilepsy at 8 months. Retterer et al, 2016 (26633542) - supp data - 2 variants identified 1 intronic del and 1 missense - primary pheno - abnormality of the mitochondrion - no further pheno information and no comments on if these are hom/het, 1 patient or 2 patients...

Created: 5 Sep 2019, 2:22 p.m. | Last Modified: 5 Sep 2019, 2:22 p.m.

Panel Version: 1.261

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Green List (high evidence)

OMIM phenotype #612949: EPILEPTIC ENCEPHALOPATHY, EARLY INFANTILE, 39. 5 DM variants on HGMDPro, associated with mitochondrial and epilepsy phenotypes. Appears to have a recessive MOI. PMID 19641205 provides a case report of an individual with AGC1 deficiency who is homozygous for p.(Gln590Arg); knockout mouse seems to recapituate human phenotype. PMID 24515575 identified a homozygous p.(Arg353Gln) variant in two siblings with profound developmental delay, congenital hypotonia, refractory epilepsy, abnormal myelination, fluctuating basal ganglia changes, cerebral atrophy, and reduced N-acetylaspartate; recombinant mutant p.(Arg353Gln) was reduced to 15% of wildtype. Two additional publications have identified SLC25A12 variants from WES with mitochondrial/epilepsy phenotype (PMID: 27290639, 26633542), phenotype information taken from HGMDPro.

Created: 23 Aug 2019, 9:58 a.m. | Last Modified: 23 Aug 2019, 9:58 a.m.

Panel Version: 1.256

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Publications

• 19641205
• 24515575
• 27290639
• 26633542

I don't know

insufficient information to assign to the Green List (only two case report). AR EIEE. Wibom et al, 2009 - 3 year old Sedish girl - seizures began at 7 months - hom variant detected, finctional expression studies showed impaired protein activity. Falk et al, 2014 - 2 sibs Indian ethnicity (consanguineous) both had seizures - hom missense variant detected - in vitro functional expression studies in E. Coli showed the mutant protein had ~15% residual activity. Pronicka et al, 2016 - Polish patient with suspected mitochondrial disorder - hom missense variant.

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 39, 612949

Publications

• 24515575
• 19641205

I don't know

Kept rating as Green based on post-Webex reviews from Helen Lord and Alison Callaway.

Created: 7 Sep 2019, 10:27 a.m. | Last Modified: 7 Sep 2019, 10:27 a.m.

Panel Version: 1.267

Review and rating 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 that were re-reviewed following the group Webex call on 2019_08_08 for Clinical Indication R59 Early onset or syndromic epilepsy.

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: Amber.

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

Panel Version: 1.189

Additional note to support Green rating: PMID:27290639, Pronicka et al, 2016 report a Polish patient (patient 24) amongst their cohort with a suspected mitochondrial disorder and a homozygous missense variant in SLC25A12. The supplementary materials notes that patient 24 had epilepsy at 8 months.

Created: 22 Jul 2019, 3:58 p.m. | Last Modified: 22 Jul 2019, 3:58 p.m.

Panel Version: 1.178

Comment when marking as ready: Associated with phenotype in OMIM and not in Gen2Phen. At least three homozygous variants identified in unrelated cases in which seizures are a phenotypic feature.

Created: 3 Dec 2018, 3:19 p.m.

Comment on publications: Homozygous missense variants: c.1058G>A; p.Arg353Gln, segregated with disease in this kindred in a child with epilepsy (PMID 24515575);
c.1769A>G, p.Gln590Arg in a 3 year old girl (PMID: 19641205); de novo in an infant c.1335C>A, p.Asn445Lys (PMID 27290639).

Created: 3 Dec 2018, 3:18 p.m.

Green List (high evidence)

Bi-alllelic variants in this gene have been associated with EE.

Created: 21 Aug 2018, 9:35 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Epileptic encephalopathy, early infantile, 39, MIM#612949

Publications

• 24515575
• 19641205
• 27290639

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