Hereditary spastic paraplegia, childhood onset

Gene: POLR3K

I don't know

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, but did not display severe spasticity, other pyramidal features, or dystonia. 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 should remain amber on this panel as spasticity was not reported in this third case (second if we count cases with the potential founder variant as one).

Created: 3 Sep 2026, 6:11 p.m. | Last Modified: 3 Sep 2026, 6:11 p.m.

Panel Version: 9.11

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