Hereditary neuropathy

Gene: POLR3A

Green List (high evidence)

Comment on mode of inheritance: There are 8 unrelated families reported with monoallelic variants and early-onset peripheral neuropathy. Hence, MOI was updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal'.

Created: 27 Jul 2026, 1:59 p.m. | Last Modified: 27 Jul 2026, 1:59 p.m.

Panel Version: 1.511

PMID:42260910 (2026) reported 11 patients from 8 unrelated families identified with heterozygous missense variants in POLR3A. The patients presented with an early-onset, progressive sensorimotor peripheral polyneuropathy with intermediate to demyelinating ranges of nerve conduction slowing, occasionally accompanied with neurological or non-neurological features. White matter abnormalities that are characteristic for the biallelic Pol III-related disorders were not observed in the brain magnetic resonance imaging.

Although biallelic variants in this gene has already been associated with phenotypes relevant for this panel on OMIM (MIM #607694, last accessed 26 July 2026) and ClinGen (with 'definitive; rating by Leukodystrophy and Leukoencephalopathy GCEP), monoallelic variants are not yet associated with relevant phenotypes in these resources.

Created: 27 Jul 2026, 1:58 p.m. | Last Modified: 27 Jul 2026, 1:58 p.m.

Panel Version: 1.510

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, OMIM:607694; leukodystrophy, hypomyelinating, 7, with or without oligodontia and/or hypogonadotropic hypogonadism, MONDO:0011897; peripheral neuropathy, MONDO:0005244

Publications

• 42260910

Green List (high evidence)

The Neurology Specialist Test Group agreed that this gene was recommended for the WGS panel based on a broader phenotype view to include conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation eg. HSP. This panel includes conditions where neuropathy is part of a more complex phenotype or where there is overlap with another neurological presentation. This panel as going to be used for R78, 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 and as a result a new panel was created https://panelapp.genomicsengland.co.uk/panels/846/ for this purpose.

Created: 7 Dec 2019, 6:08 p.m. | Last Modified: 7 Dec 2019, 6:08 p.m.

Panel Version: 1.352

Review and rating uploaded from file (Curation_Template_GMS_Neuro_AR_20190521.xlsx) submitted by Alex Rossor (UCL Institute of Neurology) on behalf of London North GLH for GMS Neurology specialist test group.

Created: 11 Jun 2019, 1:40 p.m.

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Adolescent onset progressive spastic ataxia, tremor, involvement of central sensory tracts, dental complications (hypodontia, severe peridontal disease. Bilateral hyperintensities on MRI from the superior cerebellar peduncle to the dentate nucleus / midbrain. Abnormal nerve conduction in 8 out of 14 cases.

Publications

• 28459997