Primary immunodeficiency or monogenic inflammatory bowel disease

Gene: PSMB8

Green List (high evidence)

Comment on mode of inheritance: There is sufficient evidence available (>10 unrelated families and functional work) for the association of monoallelic PSMB8 variants with proteasome-associated autoinflammatory syndrome and immunodeficiency.

Hence, the MOI should be updated to 'BOTH monoallelic and biallelic, autosomal or pseudoautosomal' in the next GMS update.

Created: 13 Aug 2026, 1:42 p.m. | Last Modified: 13 Aug 2026, 2:13 p.m.

Panel Version: 9.101

There is already sufficient evidence available for the association of biallelic variants in this gene with a relevant phenotype - associated with MIM #256040 in OMIM and with PSMB8-related Nakajo syndrome (with 'definitive' rating on the DD panel) in Gene2Phenotype (records last accessed 13 August 2026).

PMID:41253591 (2026) reported the identification of a novel de novo heterozygous PSMB8 variant, p.G209R (c.625G>A/C), identified in 8 unrelated patients (6/8 de novo, 2/8 assumed de novo) presenting with a chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature/ proteasome-associated autoinflammatory syndrome (CANDLE/ PRAAS) phenotype featuring neonatal-onset systemic inflammation, panniculitis, lipodystrophy, cytopenias (anaemia 8/8, lymphopenia and hypogammaglobulinemia 7/8), recurrent viral/bacterial/fungal infections, and porto-sinusoidal vascular liver disease with nodular regenerative hyperplasia—phenotypically broader and more severe than biallelic PSMB8-CANDLE.

Structural modelling, transfection, and knockout cell studies showed that the PSMB8 p.G209R variant sterically disrupts the β5i–β4 (PSMB2) interface, arresting propeptide processing and 20S maturation in ~75% of assembling immunoproteasomes, directly demonstrating a dominant-negative mechanism rather than simple haploinsufficiency.

PMID:42167218 (2026) reported the identification of five distinct monoallelic missense variants in PSMB8 gene in seven patients from five unrelated families with proteasome-associated autoinflammatory syndromes with immunodeficiency (PRAAS-ID). Four of these variants were inherited de novo in the respective families (although patient I7 inherited from mother (I6), for whom it is de novo), while it is inherited from their mother and mosaic (3%) in one family (patients I2/ I3). These patients presented with neonatal-onset immunodeficiency characterized by recurrent infections, B cell lymphopenia, and hypogammaglobulinemia requiring immunoglobulin replacement. Inflammatory manifestations of variable severity included enteropathy, hepatitis, myositis, and inflammatory lung disease.

Functional studies showed that monoallelic PSMB8 variants impair immunoproteasome assembly, causing ~50% loss of mature IP complexes and reduced IP-specific activity while unincorporated mutant subunits accumulate as a stalled, chaperone-bound ~440-kDa assembly intermediate, rather than simply being degraded. This structural disruption destabilizing key PSMB8-PSMB2/PSMB3 interfaces supports a dominant-negative mechanism that reduces functional immunoproteasome output and drives the combined immunodeficiency and autoinflammation seen in PRAAS-ID.

Monoallelic variants are not yet associated with any phenotypes in OMIM, Gene2Phenotype or ClinGen (last accessed 13 August 2026).

Created: 13 Aug 2026, 1:29 p.m. | Last Modified: 13 Aug 2026, 2:15 p.m.

Panel Version: 9.102

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Proteasome-associated autoinflammatory syndrome 1 and digenic forms, OMIM:256040; proteasome-associated autoinflammatory syndrome 1, MONDO:0054698; Immunodeficiency, HP:0002721

Publications

• 41253591
• 42167218

Mode of pathogenicity
Other

Comment on list classification: Changed rating of gene from Red to Green. This gene was rated as Green in v2.208 and incorrectly automatically demoted to Red in v2.209. This was due to a defect in the automatic PanelApp uploading tool when a set of publications was added to the panel with the source ‘Other’, and under certain conditions associated to previous sources listed, resulted in the rating of the gene being automatically changed when it should not have been.

Created: 14 Oct 2020, 1:42 p.m. | Last Modified: 14 Oct 2020, 1:42 p.m.

Panel Version: 2.297

The following PubMed IDs were added to gene PSMB8 (OMIM gene MIM#177046): 20159315;20534754. These publications have been associated with the gene by the autoinflammation subgroup of the Human Phenotype Ontology Immune Mediated Disorders Consortium (https://hpo-immune-mediated-disorders.groups.io/g/update) in August 2020.

Created: 13 Oct 2020, 9:36 a.m. | Last Modified: 13 Oct 2020, 9:36 a.m.

Panel Version: 2.208

Publications

• 20159315
• 20534754

Green List (high evidence)

agree with green gene

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

Green List (high evidence)

YES- this is covered on our targeted exome

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
CANDLE syndrome

Comment on list classification: Associated with relevant phenotype in OMIM and as confirmed Gen2Phen gene. At least 3 variants reported in at least 3 unrelated cases.

Created: 9 May 2018, 1:12 p.m.

Green List (high evidence)

Gene rating submitted by Kimberly Gilmour and Austen Worth on behalf of London North GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email 6th September the Specialist Test Group all agreed there is enough evidence to rate this gene Green.

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

Gene rating submitted by Tracy Briggs, David Gokhale and Abigal Rousseau on behalf of North West GLH for the GMS Immunology specialist test group. As discussed with the GMS Immunology Specialist Test Group during webex call 28th March 2019 and confirmed in follow up email on 20th June the Specialist Test Group all agreed there is enough evidence to rate this gene Green.

Created: 17 Sep 2019, 3:18 p.m. | Last Modified: 17 Sep 2019, 3:18 p.m.

Panel Version: 1.94

OriginaI Metadata from IUIS classification table (February, 2018) downloaded 20180614. IUIS Genetic defect (original gene symbol in IUIS download): PSMB8 .PanelApp HGNC gene symbol check: PSMB8 . IUIS Disease: CANDLE (chronic atypical neutrophilic dermatitis with lipodystrophy) . IUIS Inheritance: AR and AD .T cells: N/A, .B cells: N/A, .IUIS Other affected cells: N/A. IUIS Associated features: Contractures, panniculitis, ICC, fevers. IUIS Major category: Autoinflammatory Disorders. IUIS Subcategory: Type 1 Interferonopathies

Created: 2 Jul 2018, 10:35 a.m.

Comment on phenotypes: Added phenotypes suggested from external expert review.

Created: 13 Jun 2018, 11:38 a.m.

This gene was absent from the original PanelApp PID panel dataset (review April 2018). However it was listed in external expert immunodeficiency diagnostic gene list(s) GOSH or GRID. In this combined PID panel, this gene has been rated as AMBER and needs further curational review to assess pertinence prior to v1.

Created: 20 Apr 2018, 12:25 p.m.

Original metadata downloaded from ESID Registry. ESID_Gene_original: PSMB8, PanelApp HGNC gene symbol check: PSMB8, ESID classification: Main_category/ Sub_category/ PID_Diagnosis Autoinflammatory disorders / Other autoinflammatory diseases with known genetic defect / Other autoinflammatory diseases with known genetic defect

Created: 17 Apr 2018, 12:29 p.m.

Original metadata supplied by GRID. GRID Gene Symbol HGNC PanelApp check: PSMB8, GRID_Gene_Symbol: PSMB8, GRID_Transcript_ENS_Community submitted: ENST00000374882, GRID_Transcript_RefSeq: NM_004159.4, GRID_Transcript_ENS_used_on_Production: ENST00000374882

Created: 17 Apr 2018, 12:12 p.m.