TACIF - Clinical: Transmembrane Activator and CAML Interactor (TACI) Gene, Full Gene Analysis

Test Catalog

Test Name

Test ID: TACIF    
Transmembrane Activator and CAML Interactor (TACI) Gene, Full Gene Analysis

Useful For Suggests clinical disorders or settings where the test may be helpful

Evaluating individuals with:

-Common variable immunodeficiency (CVID)

-Clinically symptomatic selective IgA deficiency

-Lymphoproliferative disease associated with CVID

-Autoimmune phenotypes with CVID

 

These clinical features may be consistent with possible TACI variants, and the genotyping test is especially useful as a follow-up test when flow cytometry is uninformative.

 

Identification of specific TACI variants in individuals with abnormal TACI flow cytometry results (from IABCS / B-Cell Phenotyping Profile for Immunodeficiency and Immune Competence Assessment, Blood).

Genetics Test Information Provides information that may help with selection of the correct genetic test or proper submission of the test request

This test uses Sanger sequencing to evaluate for the presence of TNFRSF13B (TACI) variants associated with common variable immunodeficiency (CVID) and other associated conditions.

 

Targeted testing for familial variants (also called site-specific or known mutation testing) is available for this gene; see KVAR1 / Known Variant Analysis-1 Variant, or KVAR2 / Known Variant Analysis- 2 Variants. Contact Mayo Medical Laboratories at 800-533-1710 to confirm the appropriate test code for targeted testing if testing for more than 2 variants is needed.

Testing Algorithm Delineates situations when tests are added to the initial order. This includes reflex and additional tests.

 

Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test

Transmembrane activator and CAML interactor (TACI) is a member of the tumor-necrosis factor (TNF)-like receptor family, a group of receptors that regulate both survival and apoptosis of immune cells.(1) TACI is encoded by the TACI gene (official symbol, TNFRSF13B). TACI is expressed on the surface of resting B cells and activated T cells, but not resting T cells. TACI interacts with 2 ligands-BAFF (B-cell activating factor), also known as BLys (B-lymphocyte stimulator), which belongs to the TNF family, and APRIL (a proliferation-inducing ligand). The ligands for TACI are expressed on macrophages, monocytes, and dendritic cells.(2) TACI regulates isotype class-switching of immunoglobulins and also is involved in the antibody response to T-independent antigens.(3)

 

The human TACI gene locus is located on the short arm of chromosome 17, which is a common target for variation and rearrangement.(3) The TACI gene consists of 5 exons spanning approximately 35 kb (including 1002 bp upstream of the 5' untranslated region [UTR] and 1024 bp downstream of the 3' UTR). In recent studies, 4 variants (p.L69Tfs*12, p.C104R, p.A181E, p.R202H) have been shown to be statistically significant in common variable immunodeficiency (CVID) and selective IgA deficiency (sIgAD) patients when compared to controls.(4) Two other variants, p.P251L and p.V220A, are considered to be likely benign as they are present in both controls and patients.(4-6) The TACI gene variants described so far are nonsense, missense, or frameshift variants, all of which can be detected by gene sequencing.

 

CVID is a complex, heterogeneous disease with defects in 1 or more of these pathways: B-cell survival; circulating memory B cells (CD27+), including class-switched (CD27+IgM-IgD-), nonswitched (CD27+IgM+IgD+), and IgM-memory B cells (CD27+IgM+IgD-); B-cell activation after receptor cross-linking; T-cell signaling; and cytokine expression. CVID patients have hypogammaglobulinemia with impaired functional antibody responses among other clinical features. While the molecular basis for most cases of CVID and sIgAD remains unknown, a fraction of CVID cases (approximately 20%-25%) have been reported to be associated with variants in the TACI gene, ICOS, BAFF-R, or CD19. There are several other genes reported with CVID or CVID-like disease that are not discussed here. Most cases of CVID are sporadic, but at least 10% are familial with a predominance of autosomal dominant over autosomal recessive inheritance.

 

TACI gene mutations account for 8% to 15% of CVID cases depending on the study population and are sporadic in the majority of cases. The familial TACI gene variants can be inherited in either an autosomal dominant or autosomal recessive fashion. TACI gene variants can also display incomplete penetrance, indicating that not all carriers of TACI gene variants develop the disease phenotype.()7) TACI gene variants appear to be strongly associated with lymphoproliferative diseases such as splenomegaly or tonsillar hypertrophy. Autoimmune thyroiditis is observed in 15% of TACI gene variant-positive CVID cases. Heterozygous TACI gene variants are associated with CVID and autoimmunity, while homozygous TACI gene variants appears to protect against autoimmunity (8, 9).

 

The known TACI gene variants appear, in most cases, to be associated with normal protein expression with aberrant or absent functional activity. Consequently, the vast majority (approximately 95%) of cases cannot be identified by the flow cytometry analysis (see CVID / CVID Confirmation Flow Panel)). In <5% of TACI-associated CVID cases, protein expression on B cells is absent, which can be detected by flow cytometry.(10) Therefore, in the presence of a strong clinical indication for CVID and potential TACI gene variants, such as low to absent IgA levels (in the absence of anti-IgA), lymphoproliferative disease, autoimmune thyroiditis, or autoimmune cytopenias, TACI genotyping can determine if variants are present that could explain the clinical phenotype.

 

Genotyping can also be used to evaluate clinically symptomatic family members of patients with known TACI gene variants for correlation with clinical phenotype and genetic counseling (KVAR1 / Known Variant Analysis-1 Variant).

Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.

An interpretive report will be provided.

Interpretation Provides information to assist in interpretation of the test results

An interpretive report is provided that describes the variants, if any, their potential clinical significance, and whether they have been previously reported or are new variants. Variants of unknown clinical significance also will be documented in the report.

 

The published variants in the TACI gene associated with CVID are a combination of missense, nonsense, splicing, and small insertions or deletions, all of which will be detected by full gene sequencing.

Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances

Patients who have received a heterologous blood transfusion within the preceding 6 weeks, or who have received an allogeneic blood or marrow transplant, can have inaccurate genetic test results due to presence of donor DNA.

 

Only symptomatic individuals should be tested. This test should not be used for screening asymptomatic family members of patients who have a documented TACI gene variant.

 

Rare polymorphisms could potentially lead to false-negative or false-positive results. If results obtained do not match clinical findings, additional testing should be considered. Any error in the diagnosis or in the pedigree provided to the laboratory could lead to an erroneous interpretation of results.

Clinical Reference Recommendations for in-depth reading of a clinical nature

1. Mackay F, Ambrose C: The TNF family members BAFF and APRIL: the growing complexity. Cytokine Growth Factor Rev 2003;14:311-324

2. Mackay F, Schneider P, Rennert P, Browning J: BAFF and APRIL: a tutorial on B cell survival. Ann Rev Immunol 2003;21:231-264

3. Castigli E, Geha RS: Molecular basis of common variable immunodeficiency. J Allergy Clin Immunol 2006;117:740-746

4. Castigli E, Wilson S, Garibyan L, et al: Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency. Nat Genet 2007;39(4):429-431

5. Salzar U, Chapel HM, Webster ADB, et al: Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet 2005;37(8):820-828

6. Castigli E, Wilson SA, Garibyan L, et al: TACI is mutant in common variable immunodeficiency and IgA deficiency. Nat Genet 2005;37(8):829-834

7. Castilgi E, Geha RS: TACI, isotype switching, CVID and IgAD. Immunol. Res 2007;38:102-111

8. Romberg N, Chamberlain N, Saadoun D, et al: CVID-associated TACI mutations affect autoreactive B cell selection and activation. J Clin Invest 2013;123 (10):4283-4293

9. Zhang L, Radigan L, Salzer U, et al: TACI mutations in CVID: clinical and immunological outcomes in heterozygotes. J Allergy Clin Immunol 2007;120:1178-1185

10. Fried AJ, Rauter I, Dillon SR, Jabara HH, et al: Functional analysis of TACI mutations associated with common variable immunodeficiency. J Allergy Clin Immunol 2011;128(1):226-228

Special Instructions and Forms Library of PDFs including pertinent information and consent forms, specimen collection and preparation information, test algorithms, and other information pertinent to test