Ataxia and cerebellar anomalies - childhood onset

Gene: POLR3K

Green List (high evidence)

Comment on list classification: There are two unrelated cases (counting the two cases with potential founder variant as one) reported with three different variants in POLR3K (two cases homozygous for the suggested founder missense variant and one case compound heterozygous for a different missense variant and a ~17.8 kb deletion). All patients had cerebellar atrophy and two of them had ataxia. There is also functional evidence available in support of the association. Hence, this gene can be promoted to green rating in the next GMS update.

Created: 3 Sep 2026, 6:06 p.m. | Last Modified: 3 Sep 2026, 6:06 p.m.

Panel Version: 9.35

PMID:30584594 (2018) reported two unrelated patients from consanguineous Algerian families, both homozygous for c.121C>T (p.Arg41Trp) variant in POLR3K gene, with severe early-onset disease (feeding/GI dysfunction, neurodegeneration, one death at 18 years). One of these patients had ataxia and both patients had cerebellar atrophy. Functional studies in zebrafish showed that the mutation impaired the POLR3K-POLR3B interactions resulting in abnormal gut development. Functional studies in the two patients' fibroblasts revealed a severe decrease in the expression of 5S and 7S ribosomal RNAs in comparison with control.

PMID:40225923 (2024) reported a single female patient, compound heterozygous for a missense variant (c.322G>T; p.Asp108Tyr) and a large in-trans deletion (encompassing the third and last exon) in POLR3K gene, and with a much milder later-onset phenotype (onset was in late childhood/ adolescence). This includes mild intellectual and behavioural disturbances in childhood and growth delay, with brain MRI revealing diffuse hypomyelination. The patient had ataxia and cerebellar vermis atrophy. Patient fibroblasts showed markedly reduced POLR3K RNA and lower levels of several specific tRNAs, but other Pol III transcripts remained normal, indicating Pol III retains partial transcriptional function despite the variant.

This gene has been associated with relevant phenotype in OMIM (MIM #619310) and the record was last accessed 03 September 2026. This gene is also associated with leukodystrophy, hypomyelinating, 21 (MONDO:0030263) by Leukodystrophy and Leukoencephalopathy GCEP in ClinGen, but with 'Limited' rating (https://search.clinicalgenome.org/CCID:009053)

Created: 3 Sep 2026, 6:02 p.m. | Last Modified: 3 Sep 2026, 6:02 p.m.

Panel Version: 9.32

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Leukodystrophy, hypomyelinating, 21, OMIM:619310; leukodystrophy, hypomyelinating, 21, MONDO:0030263

Publications

• 30584594
• 40225923

Comment on list classification: New gene added by Zornitza Stark (Australian Genomics). This gene is associated with a relevant phenotype in OMIM but not in Gene2Phenotype.

PMID: 30584594. 2 affected individuals from 2 consanguineous families from same area in Algeria. Affected indviduals had global developmental delay with loss of motor, speech and cognitive milestones. Individuals also showed signs of nystagmus, ataxia, dystonia and spasticity. Both individuals had feeding difficulties and were tube fed, growth failure and microcephaly (-3 SD), and cryptorchidism. 1 patient had optic atrophy and hypodontia and the other patient had hypogonadotropic hypogonadism. Both individuals have the same variant (may be founder effect).

As other members of the same gene family are linked to similar phenotypes this gene has been given an Amber rating.

Created: 19 May 2021, 10:07 a.m. | Last Modified: 19 May 2021, 10:07 a.m.

Panel Version: 1.98

I don't know

Two individuals from same ethnic background reported with a common homozygous missense variant in this gene, suggestive of founder effect. Some functional evidence, and note other gene family members are linked to similar phenotypes.

Neurodegenerative phenotype: global developmental delay apparent from infancy with loss of motor, speech, and cognitive milestones in the first decades of life.
Sources: Literature

Created: 10 May 2021, 10:23 a.m.

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Hypomyelinating leukodystrophy-21, MIM#619310

Publications

• 30584594
• 33659930