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Common Variable Immune Deficiency/IgA Deficiency via the TNFRSF13B 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
8731 TNFRSF13B 81479 81479,81479 $890 Order Options and Pricing
Test Code Test Copy Genes Test CPT Code Gene CPT Codes Copy CPT Code Base Price
8731TNFRSF13B81479 81479,81479 $890 Order Options and Pricing

Pricing Comments

Our favored testing approach is exome based NextGen sequencing with CNV analysis. This will allow cost effective reflexing to PGxome or other exome based tests. However, if full gene Sanger sequencing is desired for STAT turnaround time, insurance, or other reasons, please see link below for Test Code, pricing, and turnaround time information. If the Sanger option is selected, CNV detection may be ordered through Test #600.

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).

The Sanger Sequencing method for this test is NY State approved.

For Sanger Sequencing click here.

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

  • Megan Piazza, PhD, FACMG

Clinical Features and Genetics

Clinical Features

Common Variable Immune Deficiency (CVID) is a disorder characterized by impaired humoral immunity resulting in infection susceptibility. Symptom onset is typically from age two to early adulthood with CVID affecting approximately one in 25,000 births, making it the most prevalent primary immunodeficiency. The most common genetic cause of CVID is mutation in the TNFRSF13B gene which accounts for 15-20% of cases (Salzer et al. 2005; Castigli et al. 2005). CVID may also be caused through mutations in the ICOS, BAFFR or CD19 genes and represent <1% of cases. Mutations in the TNFRSF13B gene also cause a phenotypically similar disorder, IgA Deficiency (IgAD). Genetic testing is helpful in differential diagnosis from other similar immunodeficiencies including agammaglobulinemia, ataxia-telangiectasia, severe combined immunodeficiency, WHIM syndrome, Wiskott-Aldrich syndrome, and X-linked lymphoproliferative disease (see related tests for detailed information on individual disorders). Treatment of CVID often includes immunoglobulin replacement therapy but may include splenectomy (Scharenberg et al. 2006; Wong et al. 2013). Patients with CVID through mutation in the TNFRSF13B gene are inherently susceptible to lymphoma. Therefore, genetic testing is helpful in determining if periodic CBC and WBC counts are required for surveillance of lymphoma (da Silva et al. 2011).

Genetics

In 75% of CVID cases, the genetic underpinnings are unknown. The remaining cases of CVID are inherited in an autosomal dominant manner through mutations in the TNFRSF13B (15-20%) gene or an autosomal recessive mode through mutations in the ICOS, BAFFR, or CD19 genes (Scharenberg et al. 2006; Castigli and Geha 2006; Salzer et al. 2005). In rare cases, CVID has been shown to be inherited in an autosomal recessive manner through TNFRSF13B gene mutations. Mutations are found throughout the TNFRSF13B gene in CVID patients with about 90% of cases being sporadic. Two missense mutations, c.310T>C (p.Cys104Arg) and c.542C>A (p.Ala181Glu) are most commonly found and represent about 80% of all CVID cases through TNFRSF13B mutations (Salzer et al. 2009). Nonsense, splicing alterations, small insertions and small deletions have also been reported in a few cases (Salzer et al. 2009). While severity of symptoms may vary, disease penetrance is complete (Scharenberg et al. 2006).

The TNFRSF13B gene encodes the B-cell tumor necrosis factor surface receptor, transmembrane activator, and CAML interactor. Signaling by the APRIL and BAFF ligands through this receptor in conjunction with cytokine stimulation of the B-cell is required for antibody class switching which important for strengthening immunity during infection (Castigli et al. 2005).

Clinical Sensitivity - Sequencing with CNV PGxome

Three separate reports were able to identify causative mutations in the TNFRSF13B gene in 50 of 564 (9%) patients with hypogammaglobulinemia, 5 of 20 (25%) individuals with CVID, and 13 of 162 (8%) individuals with CVID (Salzer et al. 2009; Castigli et al. 2005; Salzer et al. 2005). In 75-80% of cases with CVID, the cause is unknown (Scharenberg et al. 2006). Analytical sensitivity should be very high as all causative variants reported to date for CVID and IgAD are detectable by this methodology.

Testing Strategy

This test provides full coverage of all coding exons of the TNFRSF13B 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).

Indications for Test

Patients with CVID typically present with low serum IgG and IgA levels, recurrent Streptococcus pneumonia, Hemophilis influenza, and/or Klebsiella pneumonia infections. Other indicators of CVID include reduced CD4 T-cell counts, nodular lymphoid hyperplasia, auto-immune pneumonia, and recurrent gastrointestinal infections including Salmonella, Campylobacter, and/or Giardia (Scharenberg et al. 2006). This test may also be considered for the reproductive partners of individuals who carry pathogenic variants in TNFRSF13B.

Gene

Official Gene Symbol OMIM ID
TNFRSF13B 604907
Inheritance Abbreviation
Autosomal Dominant AD
Autosomal Recessive AR
X-Linked XL
Mitochondrial MT

Diseases

Name Inheritance OMIM ID
Common Variable Agammaglobulinemia AR, AD 240500
Immunoglobulin A Deficiency 2 AR, AD 609529

Citations

  • Castigli E, Geha R. 2006. Molecular basis of common variable immunodeficiency. Journal of Allergy and Clinical Immunology 117: 740–746. PubMed ID: 16630927
  • Castigli E, Wilson SA, Garibyan L, Rachid R, Bonilla F, Schneider L, Geha RS. 2005. TACI is mutant in common variable immunodeficiency and IgA deficiency. Nature Genetics 37: 829–834. PubMed ID: 16007086
  • da Silva SP, Resnick E, Lucas M, Lortan J, Patel S, Cunningham-Rundles C, Gatter K, Liu Q, Jaffe ES, Chapel H. 2011. Lymphoid Proliferations of Indeterminate Malignant Potential arising in Adults with Common Variable Immunodeficiency Disorders: Unusual Case Studies and Immunohistological Review in the Light of Possible Causative Events. Journal of Clinical Immunology 31: 784–791. PubMed ID: 21744182
  • Salzer U, Bacchelli C, Buckridge S, Pan-Hammarström Q, Jennings S, Lougaris V, Bergbreiter A, Hagena T, Birmelin J, Plebani A, others. 2009. Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes. Blood 113: 1967–1976. PubMed ID: 18981294
  • Salzer U, Chapel HM, Webster ADB, Pan-Hammarström Q, Schmitt-Graeff A, Schlesier M, Peter HH, Rockstroh JK, Schneider P, Schäffer AA, Hammarström L, Grimbacher B. 2005. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nature Genetics 37: 820–828. PubMed ID: 16007087
  • Scharenberg AM, Hannibal MC, Torgerson T, Ochs HD, Rawlings DJ. 2006. Common Variable Immune Deficiency Overview. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong C-T, Smith RJ, and Stephens K, editors. GeneReviews(®), Seattle (WA): University of Washington, Seattle. PubMed ID: 20301476
  • Wong GK, Goldacker S, Winterhalter C, Grimbacher B, Chapel H, Lucas M, Alecsandru D, McEwen D, Quinti I, Martini H, Schmidt RE, Ernst D, et al. 2013. Outcomes of splenectomy in patients with common variable immunodeficiency (CVID): a survey of 45 patients: Splenectomy in CVID. Clinical & Experimental Immunology 172: 63–72. PubMed ID: 23480186

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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