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CANDLE Syndrome via the PSMB4 Gene

Summary and Pricing

Test Method

Exome Sequencing with CNV Detection
Test Code Test Copy GenesTest CPT Code Gene CPT Codes Copy CPT Codes Base Price
13019 PSMB4 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
13019PSMB481479 81479(x2) $890 Order Options and Pricing

An additional 25% charge will be applied to STAT orders. STAT orders are prioritized throughout the testing process.

Click here for costs to reflex to whole PGxome (if original test is on PGxome Sequencing backbone).

Click here for costs to reflex to whole PGnome (if original test is on PGnome Sequencing backbone).

Turnaround Time

18 days on average for standard orders or 13 days on average for STAT orders.

Please note: Once the testing process begins, an Estimated Report Date (ERD) range will be displayed in the portal. This is the most accurate prediction of when your report will be complete and may differ from the average TAT published on our website. About 85% of our tests will be reported within or before the ERD range. We will notify you of significant delays or holds which will impact the ERD. Learn more about turnaround times here.

Targeted Testing

For ordering sequencing of targeted known variants, go to our Targeted Variants page.

EMAIL CONTACTS

Genetic Counselors

Geneticist

  • McKenna Kyriss, PhD

Clinical Features and Genetics

Clinical Features

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.

Genetics

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).

Clinical Sensitivity - Sequencing with CNV PGxome

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.

Testing Strategy

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).

Indications for Test

Candidates for this test are patients with clinical features consistent with a diagnosis of CANDLE syndrome. Targeted testing is indicated for family members of patients who have a known pathogenic variant in PSMB4. This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in PSMB4.

Gene

Official Gene Symbol OMIM ID
PSMB4 602177
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Citations

Ordering/Specimens

Ordering Options

We offer several options when ordering sequencing tests. For more information on these options, see our Ordering Instructions page. To view available options, click on the Order Options button within the test description.

myPrevent - Online Ordering

  • The test can be added to your online orders in the Summary and Pricing section.
  • Once the test has been added log in to myPrevent to fill out an online requisition form.
  • PGnome sequencing panels can be ordered via the myPrevent portal only at this time.

Requisition Form

  • A completed requisition form must accompany all specimens.
  • Billing information along with specimen and shipping instructions are within the requisition form.
  • All testing must be ordered by a qualified healthcare provider.

For Requisition Forms, visit our Forms page


Specimen Types

Specimen Requirements and Shipping Details

PGxome (Exome) Sequencing Panel

PGnome (Genome) Sequencing Panel

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ORDER OPTIONS

View Ordering Instructions

1) Select Test Method (Backbone)


1) Select Test Type


2) Select Additional Test Options

STAT and Prenatal Test Options are not available with Patient Plus.

No Additional Test Options are available for this test.

Note: acceptable specimen types are whole blood and DNA from whole blood only.
Total Price: $
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