CANDLE Syndrome via the PSMB8 Gene

Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature (CANDLE) syndrome is a rare autoinflammatory disease due to impairment of proteasome function. Symptom onset occurs within the first two weeks to 6 months of life with recurrent fevers, violaceous cutaneous plaques covering trunk and extremities, swollen eyelids, thick lips, and facial lipodystrophy. Patients also can present with conjunctivitis, delayed physical development, joint pain without arthritis, chondrites of the ear and nose, myositis, hepatosplenomegaly, microcytic anemia, and muscle atrophy. In severe cases, inflammatory attacks can result in organ failure and sudden death. Genetic testing is helpful in the differential diagnosis of CANDLE from other autoinflammatory syndromes including cryopyrin-associated periodic syndromes (CAPS), Majeed syndrome, and Hyper IgD syndrome (Sanchez et al. 2013; Arima et al. 2011; Kluk et al. 2014; Agarwal et al. 2010; Liu et al. 2012).

CANDLE syndrome is inherited in an autosomal recessive manner through pathogenic variants in the PSMB8 gene. Missense variants, found throughout the protein, have been reported in all but one case. The exception was a patient homozygous for a nonsense variant (Sanchez et al. 2013; Arima et al. 2011; Kluk et al. 2014; Agarwal et al. 2010; Liu et al 2012). The PSMB8 gene encodes the β5i proteasome subunit which is involved in degrading ubiquitin tagged proteins. Missense variants in the PSMB8 gene result in incorporation of other proteasome subunits to the complex resulting in heightened inflammatory signaling (Arima et al. 2011).

Clinical sensitivity cannot be estimated because only a small number of cases have been reported to date. Analytical sensitivity should be high as all pathogenic variants reported to date are detectable by sequencing.

No large deletions or duplications involving PSMB8 have been reported (Human Gene Mutation Database).

This test provides full coverage of all coding exons of the PSMB8 gene plus 10 bases of flanking noncoding DNA in all available transcripts along with other 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).