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Intellectual disability

Gene: PSMF1

Amber List (moderate evidence)
PSMF1 (proteasome inhibitor subunit 1)
EnsemblGeneIds (GRCh38): ENSG00000125818
EnsemblGeneIds (GRCh37): ENSG00000125818
PSMF1 is in 5 panels

1 review

Ida Ertmanska (Genomics England Curator)

Green List (high evidence)

Comment on list classification: There are 9 individuals from 4 unrelated families reported in literature with biallelic PSMF1 splice variants and a childhood-onset syndromic neurological disorder, primarily characterised by Parkinsonian-pyramidal syndrome, developmental delay, and corpus callosum hypoplasia. Intellectual disability was noted in 3/4 families, with mild/borderline ID in one of them. In addition, 3 probands with biallelic predicted LoF variants in PSMF1 presented with arthrogryposis and global developmental delay in the first years of life. Hence, this gene can be promoted to Green on Intellectual disability.
Created: 4 Nov 2026, 2:52 p.m. | Last Modified: 4 Nov 2026, 2:52 p.m.
Panel Version: 11.81
PMID: 41986367 Magrinelli et al., 2026
Report of 18 unrelated families of European, Asian and African ancestry with 25 affected subjects harbouring biallelic PSMF1 missense and loss-of-function variants. Consanguinity was reported in 11/18 families. Probands’ parents were healthy. Patient phenotypes ranged from early-onset PD to perinatal lethality with neurological manifestations.
In 8 families, 10 individuals presented with early-onset Parkinson disease. 5 individuals had disease onset at age 18 years or under, 4 others were aged 19-29 years, and 1 individual had disease onset at 48 years. These individuals harboured homozygous missense variants, or comp het homozygous + LoF.
In 4 families the presentation consisted of miscellaneous movement disorders, encompassing parkinsonism, moderate-to-severe pyramidal tract signs, ataxia or a combination thereof, with mild-to-moderate intellectual disability, epilepsy and cognitive decline. Cerebellar malformations/atrophy were noted on MRI in 4 individuals. Age of onset was under 12 years of age for this subgroup. All 4 probands were homozygous for splice variants in PSMF1.
Finally, in 4 families, the core phenotype was arthrogryposis, with poor feeding, respiratory insufficiency, corpus callosum malformations and early lethality. Global developmental delay was reported in all 3 probands surviving past 2 months of age. Biallelic LoF variants are thought to cause this most severe presentation.
Functional evidence: Drosophila and mouse models showed age-dependent motor impairment, brain-wide mitochondrial membrane depolarization and dopaminergic neurodegeneration in aged flies, and diffuse gliosis in mice.

PSMF1 is associated with Parkinson disease 27, autosomal recessive early-onset, OMIM:621693, AR Arthrogryposis multiplex congenita 8, neurogenic type, OMIM:621695, and Neurodegeneration, childhood-onset, with movement disorders, cognitive decline, and brain abnormalities, OMIM:621694, and AR (OMIM accessed 4th Nov 2026).
Sources: Literature
Created: 4 Nov 2026, 2:44 p.m. | Last Modified: 4 Nov 2026, 2:46 p.m.
Panel Version: 11.80

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Neurodegeneration, childhood-onset, with movement disorders, cognitive decline, and brain abnormalities, OMIM:621694; Arthrogryposis multiplex congenita 8, neurogenic type, OMIM:621695

Publications

Created: 4 Nov 2026, 2:44 p.m.
Last Modified: 4 Nov 2026, 2:46 p.m.
Panel version: 11.80

Details

Mode of Inheritance
BIALLELIC, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
  • Literature
Phenotypes
  • Neurodegeneration, childhood-onset, with movement disorders, cognitive decline, and brain abnormalities, OMIM:621694
  • Arthrogryposis multiplex congenita 8, neurogenic type, OMIM:621695
Tags
Q4_26_promote_green
Clinvar variants
Variants in PSMF1
Penetrance
None
Publications
Panels with this gene

History Filter Activity

4 Nov 2026, Gel status: 2

Set Phenotypes

Ida Ertmanska (Genomics England Curator)

Phenotypes for gene: PSMF1 were changed from Parkinson disease 27, autosomal recessive early-onset, OMIM:621693; young-onset Parkinson disease, MONDO:0017279; arthrogryposis, MONDO:0008779 to Neurodegeneration, childhood-onset, with movement disorders, cognitive decline, and brain abnormalities, OMIM:621694; Arthrogryposis multiplex congenita 8, neurogenic type, OMIM:621695

4 Nov 2026, Gel status: 2

Entity classified by Genomics England curator

Ida Ertmanska (Genomics England Curator)

Gene: psmf1 has been classified as Amber List (Moderate Evidence).

4 Nov 2026, Gel status: 1

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

Ida Ertmanska (Genomics England Curator)

gene: PSMF1 was added gene: PSMF1 was added to Intellectual disability. Sources: Literature Q4_26_promote_green tags were added to gene: PSMF1. Mode of inheritance for gene: PSMF1 was set to BIALLELIC, autosomal or pseudoautosomal Publications for gene: PSMF1 were set to 41986367 Phenotypes for gene: PSMF1 were set to Parkinson disease 27, autosomal recessive early-onset, OMIM:621693; young-onset Parkinson disease, MONDO:0017279; arthrogryposis, MONDO:0008779 Review for gene: PSMF1 was set to GREEN