Lipodystrophy - childhood onset

Gene: PSMB4

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 31 Dec 2025, 7:17 p.m. | Last Modified: 31 Dec 2025, 7:17 p.m.

Panel Version: 4.66

This gene is approved to upgrade to Green when TD eligibility and Clinical Indication name is expanded to Severe insulin resistance and lipodystrophy syndromes.

Created: 17 Jun 2024, 8:59 a.m. | Last Modified: 17 Jun 2024, 8:59 a.m.

Panel Version: 4.54

The 'digenic' tag has been added as there are four additional cases with heterozygous PSMB4 variants and heterozygous variants in either PSMA3 and PSMB8.

Created: 8 Aug 2023, 11:33 a.m. | Last Modified: 8 Aug 2023, 11:33 a.m.

Panel Version: 4.40

Comment on list classification: There is sufficient evidence for the association of biallelic variants in PSMB4 with lipodystrophy (two unrelated cases and supporting functional evidence). Hence, this gene can be promoted to green rating in the next GMS review.

Created: 8 Aug 2023, 11:31 a.m. | Last Modified: 8 Aug 2023, 11:31 a.m.

Panel Version: 4.40

PMID:26524591 - One case with compound heterozygous variants in PSMB4 (monogenic), two cases with heterozygous variants in PSMB4 and PSMB8 (digenic) and two cases with heterozygous variants in PSMB4 and PSMB9 (digenic) were reported with proteasome-associated autoinflammatory syndrome (PRAAS) that includes lipodystrophy and lipid abnormalities. In addition, it was revealed from functional studies that these variants affect transcription, protein expression, protein folding, proteasome assembly, and, ultimately, proteasome activity.

PMID:34416217 - A boy with treatment-resistant cutaneous vasculitis was identified with novel heterozygous variants in PSMB4. This patient developed mild lipodystrophy after the successful second hematopoietic stem cell transplantation (HSCT).

This gene has been associated with PRAAS in OMIM and it includes lipodystrophy as one of the clinical manifestations.

Created: 8 Aug 2023, 11:28 a.m. | Last Modified: 8 Aug 2023, 11:36 a.m.

Panel Version: 4.40

This gene was added on recommendation of NHSE Genomic Medicine Service:
These autoinflammatory syndromes include a lipodystrophy (partial and generalised have both been reported) and are caused either by biallelic loss of function mutations (PMID: 26524591, 34416217) or by digenic heterozygous mutations in other proteasome encoding genes (PSMB8, PMSA3 PMID: 26524591). See panel app reviews for autoinflammatory syndromes.

PSMB9 has also been implicated in digenic cases but this is in a single familes and lipodystrophy is not reported in the autoinflammatory syndrome of carriers of biallelic loss of function mutations in PSMB9.

Created: 2 Aug 2023, 11:35 a.m. | Last Modified: 8 Aug 2023, 10:52 a.m.

Panel Version: 4.37

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
Proteasome associated autoinflammatory syndrome-1, CANDLES (Chronic, atypical, neutrophillic dermatosis with lipodystrophy and elevated temperature syndrome), Joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP syndrome)

Publications

• 26524591
• 34416217