CANDLE Syndrome via the PSMB4 Gene

Pathogenic variants in the PSMB4 gene are associated with chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome, a rare autoinflammatory disorder of impaired proteasome function (Brehm et al. 2015. PubMed ID: 26524591). PSMB4-associated CANDLE syndrome is also referred to as proteasome-associated autoinflammatory syndrome (PRAAS). Clinical features may include recurrent fevers, nodular skin rashes or lesions (particularly around the eyes and eyelids), myositis, arthritis or arthralgia, joint contractures, lymphadenopathy, partial lipodystrophy, facial edema, hepatosplenomegaly, basal ganglion calcifications, growth failure, and recurrent infections (Brehm et al. 2015. PubMed ID: 26524591). Laboratory anomalies may include elevated acute phase reactants, hypergammaglobulinemia, anemia, thrombocytopenia, lymphopenia, abnormal lipid profiles, and intermittent elevations of autoantibodies (Brehm et al. 2015. PubMed ID: 26524591). It should be noted that a limited number of cases have been reported and that some features may be variable. Onset is reported to occur during the neonatal period with an initial presentation of fever and skin rashes or lesions. The exact prevalence of CANDLE syndrome is presently unknown, but is considered rare.

CANDLE syndrome is also associated with pathogenic variants in several other genes including PSMA3, PSMB8, and PSMB9. The clinical features and presentation also displays overlap with the lipodystrophies and several autoinflammatory syndromes. Genetic testing may aide in establishing a differential diagnosis and may assist reproductive planning.

Pathogenic variants in the PMSB4 gene are associated with autosomal recessive CANDLE syndrome. A promoter variant, an in-frame deletion, a frameshift and a nonsense variant have been reported in 5 individuals with CANDLE syndrome from 3 families (Brehm et al. 2015. PubMed ID: 26524591). The 5 individuals included one individual with compound heterozygous PSMB4 pathogenic variants, two siblings each harboring a paternal PSMB4 pathogenic variant and a maternal PSMB9 pathogenic variant, and another set of siblings each harboring a paternal PSMB4 pathogenic variant and a maternal PSMB8 pathogenic variant (Brehm et al. 2015. PubMed ID: 26524591). Functional studies supported a digenic model for disease in both sets of affected siblings (Brehm et al. 2015. PubMed ID: 26524591). To date, all pathogenic variants have been inherited from a carrier parent. No structural variants have been reported.

The PSMB4 gene encodes the beta subunit of the human 26S proteasome (Gerards et al. 1994. PubMed ID: 8013624). The 26S proteasome is the endpoint for the ubiquitin-proteasome system. It is responsible for regulated protein degradation in the cytosol and nucleus and is essential for protein and amino acid homeostasis as well as many other cellular processes (Bard et al. 2018. PubMed ID: 29652515). Functional studies suggest that PSMB4 CANDLE Syndrome-associated variants disrupt normal proteasome function, which leads to Interferon dysregulation triggering a severe autoinflammatory response (Brehm et al. 2015. PubMed ID: 26524591).

The clinical sensitivity of CANDLE syndrome is difficult to estimate, as to date, a limited number of cases have been described in the literature (Torrelo et al. 2010. PubMed ID: 20159315; Liu et al. 2012. PubMed ID: 21953331; Kluk et al. 2014. PubMed ID: 24001180; Brehm et al. 2015. PubMed ID: 26524591; Boyadzhiev et al. 2019. PubMed ID: 31046790). Analytical sensitivity should be high as all pathogenic variants reported to date are detectable by sequencing.

This test is performed using Next-Gen sequencing with additional Sanger sequencing as necessary.

This test provides full coverage of all coding exons of the PSMB4 gene plus 10 bases flanking noncoding DNA in all available transcripts in addition to non-coding regions in which pathogenic variants have been identified at PreventionGenetics or reported elsewhere. We define full coverage as ≥20X NGS reads or Sanger sequencing. PGnome panels typically provide slightly increased coverage over the PGxome equivalent. PGnome sequencing panels have the added benefit of additional analysis and reporting of deep intronic regions (where applicable).

Dependent on the sequencing backbone selected for this testing, discounted reflex testing to any other similar backbone-based test is available (i.e., PGxome panel to whole PGxome; PGnome panel to whole PGnome).