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Genetic epilepsy syndromes

Gene: POLG2

Amber List (moderate evidence)

POLG2 (DNA polymerase gamma 2, accessory subunit)
EnsemblGeneIds (GRCh38): ENSG00000256525
EnsemblGeneIds (GRCh37): ENSG00000256525
OMIM: 604983, Gene2Phenotype
POLG2 is in 14 panels

3 reviews

Rebecca Foulger (Genomics England curator)

Comment on mode of inheritance: Kept rating as Amber to match Helen Lord's review, but changed MOI from biallelic to 'BOTH biallelic and monoallelic' since (as Helen Lord notes) Young et al 2011 (PMID:21555342) report 4/11 patients with seizures as part of their phenotype and heterozygous variants in POLG2.
Created: 30 Sep 2019, 3:02 p.m. | Last Modified: 30 Sep 2019, 3:02 p.m.
Panel Version: 1.344

Helen Lord (Oxford Medical Genetics Laboratories)

I don't know

On OMIM this gene is associated with AD PEOA4 - Young et al 2011 (21555342) - 4/11 unrelated patients had seizures as part of there phenotype. Biochemical findings suggest that P205R (patient had refractory seizures) and the R369G p55 variants have moderate defects in processivity, while the L475DfsX2 truncation (patient had seizures) displays severe defects in p140 binding, dsDNA binding and structural integrity. AR Mitochondrial DNA deletion syndrome 16 (hepatic type) - Varma et al, 2016 (27592148) - hom missense variant detected, parents obligate carriers - no epilepsy phenotype in patient, did die at 9 months of age of hepatic failure Hoff et al, 2018 (30157269) - characterisation of the variant identified by Varma et al. 2019 paper linking this gene to AR epilepsy without ophthalmoplegia - Lee et al, 2019 (31286721) - Pakistani family - proband had focal epileptic seizures and his deceased younger brother had also had intractable seizures. Neither parent had liver disease or ophthalmoplegia and both parents were unaffected. The proband and his brother were hom for the G232S variant (WES) - classed as likely pathogenic. Therefore AD and AR associated with an epilepsy phenotype.
Created: 23 Sep 2019, 1:20 p.m. | Last Modified: 23 Sep 2019, 1:20 p.m.
Panel Version: 1.336

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Publications

Sarah Leigh (Genomics England Curator)

I don't know

Comment on list classification: Single case of recessive epilepsy.
Created: 8 Aug 2019, 11:40 a.m. | Last Modified: 8 Aug 2019, 11:40 a.m.
Panel Version: 1.198
Single case of Autosomal Recessive Epilepsy Family Without Ophthalmoplegia in a 27-year-old Pakistani male, who was homozygous for POLG2 c.694G>A, p.G232S. Both his parents were heterozygous for this variant, and none of them had liver disease, ophthalmoplegia, ptosis, nystagmus, or myopathy, and the parents showed no symptoms of epilepsy or ophthalmoplegia.
Sources: Literature
Created: 8 Aug 2019, 11:38 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Autosomal Recessive Epilepsy Family Without Ophthalmoplegia

Publications

Details

Mode of Inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
  • Literature
Phenotypes
  • Mitochondrial DNA depletion syndrome 16 (hepatic type), 618528
  • Autosomal Recessive Epilepsy Family Without Ophthalmoplegia
  • Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, 610131
OMIM
604983
Clinvar variants
Variants in POLG2
Penetrance
None
Publications
Panels with this gene

History Filter Activity

30 Sep 2019, Gel status: 2

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: POLG2 were changed from Autosomal Recessive Epilepsy Family Without Ophthalmoplegia; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, 610131 to Mitochondrial DNA depletion syndrome 16 (hepatic type), 618528; Autosomal Recessive Epilepsy Family Without Ophthalmoplegia; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, 610131

30 Sep 2019, Gel status: 2

Set Phenotypes

Rebecca Foulger (Genomics England curator)

Phenotypes for gene: POLG2 were changed from Autosomal Recessive Epilepsy Family Without Ophthalmoplegia to Autosomal Recessive Epilepsy Family Without Ophthalmoplegia; Progressive external ophthalmoplegia with mitochondrial DNA deletions, autosomal dominant 4, 610131

30 Sep 2019, Gel status: 2

Set mode of inheritance

Rebecca Foulger (Genomics England curator)

Mode of inheritance for gene: POLG2 was changed from BIALLELIC, autosomal or pseudoautosomal to BOTH monoallelic and biallelic, autosomal or pseudoautosomal

26 Sep 2019, Gel status: 2

Set publications

Rebecca Foulger (Genomics England curator)

Publications for gene: POLG2 were set to 31286721; 27592148; 30157269

8 Aug 2019, Gel status: 2

Entity classified by Genomics England curator

Sarah Leigh (Genomics England Curator)

Gene: polg2 has been classified as Amber List (Moderate Evidence).

8 Aug 2019, Gel status: 1

Created, Added New Source, Set mode of inheritance, Set publications, Set Phenotypes

Sarah Leigh (Genomics England Curator)

gene: POLG2 was added gene: POLG2 was added to Genetic epilepsy syndromes. Sources: Literature Mode of inheritance for gene: POLG2 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: POLG2 were set to 31286721; 27592148; 30157269 Phenotypes for gene: POLG2 were set to Autosomal Recessive Epilepsy Family Without Ophthalmoplegia Review for gene: POLG2 was set to AMBER