Hereditary neuropathy or pain disorder

Gene: POLG

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 24 Feb 2025, 5:02 p.m. | Last Modified: 24 Feb 2025, 5:02 p.m.

Panel Version: 6.148

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Green List (high evidence)

Comment on list classification: As reviewed by Alexander Rossor, peripheral neuropathy is a well-established feature of POLG disease and hence this gene should be promoted to green rating in the next GMS update.

Created: 6 Nov 2024, 1:34 p.m. | Last Modified: 6 Nov 2024, 1:34 p.m.

Panel Version: 6.124

PMID:12975295 reported four unrelated patients with progressive external ophthalmoplegia (PEO) and with POLG variants. Of three patients with heterozygous variants, one had neuropathy and the only patient with compound heterozygous variants also had neuropathy.

PMID:15534189 reported a family with monoallelic missense variant in POLG gene and with progressive external ophthalmoplegia, neuropathy, hypogonadism, and parkinsonism.

PMID:19752458 reported 26 patients from 23 families with cerebellar ataxia plus sensory neuropathy or external ophthalmoplegia. Of these 15 patients from 11 families were identified with POLG variants, of which four patients from two families had heterozygous variants and 11 patients from nine families had either homozygous or compound heterozygous variants.

PMID:25281868 reported 116 patients with genetically-defined mitochondrial disease and progressive external ophthalmoplegia, of which 16 patients had a large-fibre peripheral neuropathy. Eight of them were identified with biallelic PLOG variants and one of them was identified with POLG monoallelic variant.

PMID:33791913 reported a patient with sensory ataxic neuropathy, dysarthria, and ophthalmoparesis (SANDO) and was identified with two novel missense variants. A systematic review of previous literature in this publication summarised a total of 35 distinct variants from POLG are reported in 63 patients with SANDO. All of them had the variants either in homozygous or compound heterozygous state.

PMID:36703500 reported gait disturbance related to sensory ataxia and oculomotor abnormalities in four patients with biallelic POLG variants. They all had sensory axonal neuropathy.

PMID:38975049 reported a retrospective study of 40 children carrying biallelic pathogenic POLG variants, of which sensorimotor axonal neuropathy was present in eight children (20%) and polyradiculoneuropathy was present in six children (15%).

Both monoallelic and biallelic variants of this gene are associated with relevant phenotypes in OMIM and Gene2Phenotype (DD and eye panels) and OMIM records neuropathy as a clinical presentation of all but one phenotypes.

Created: 6 Nov 2024, 12:40 p.m. | Last Modified: 6 Nov 2024, 1:31 p.m.

Panel Version: 6.121

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Mitochondrial DNA depletion syndrome 4B (MNGIE type), OMIM:613662; Mitochondrial recessive ataxia syndrome (includes SANDO and SCAE), OMIM:607459; Progressive external ophthalmoplegia, autosomal dominant 1, OMIM:157640; Progressive external ophthalmoplegia, autosomal recessive 1, OMIM:258450

Publications

• 12975295
• 15534189
• 19752458
• 25281868
• 33791913
• 36703500
• 38975049

I don't know

Comment on list classification: Gene included in a list of complex neuropathy syndrome genes recommended to be downgraded for R78 panel (list submitted by Alex Rossor 15th July 2019)

Created: 6 Dec 2019, 8:26 p.m. | Last Modified: 6 Dec 2019, 8:26 p.m.

Panel Version: 0.64

This gene has changed ratings because the panel for R78 was going to be a broad panel (to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP) but subsequently during the follow up call on 21st June with the Test Group it was agreed that it was more clinically relevant for R78 to be restricted to genes that are associated with isolated neuropathy, which this panel represents. For genes that represent the broader phenotype see https://panelapp.genomicsengland.co.uk/panels/85/.

Created: 6 Dec 2019, 8:25 p.m. | Last Modified: 6 Dec 2019, 8:25 p.m.

Panel Version: 0.63

Rating and review submitted on behalf of James Polke (Neurogenetics Laboratory,Institute of Neurology, London), on behalf of London North GLH for GMS Neurology specialist test group.

Created: 9 May 2019, 5 p.m.

Green List (high evidence)

Green List (high evidence)

Now R78 includes complex phenotypes this needs to be included as PN well established in POLG disease

Created: 20 Oct 2024, 10:31 a.m. | Last Modified: 20 Oct 2024, 10:31 a.m.

Panel Version: 5.19

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
peripheral neuropathy; CPEO

Publications

• 36703500 : 33791913: 25281868: 38975049

Green List (high evidence)

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Comment on list classification: Promoted from red to green due to agreement from 3 reviewers. It is a confirmed DD gene for Mitochondrial DNA depletion syndrome 4A.

Created: 5 May 2016, 9:27 a.m.

Green List (high evidence)

SANDO is a typical presentation

Created: 9 Dec 2015, 4:48 p.m.

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