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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 mutations, and the genotyping test is especially useful as a follow-up test when flow cytometry is uninformative.
Identification of specific TACI mutations in individuals with abnormal TACI flow cytometry results (from IABCS / B-Cell Phenotyping Profile for Immunodeficiency and Immune Competence Assessment, Blood).
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 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)
TACI is encoded by the TACI gene (official symbol, TNFRSF13B). The human TACI gene locus is located on the short arm of chromosome 17, which is a common target for mutation 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). The mRNA length is 1377 bp, encoding for a 294-amino acid protein with a molecular weight of 32.34 kD. In recent studies, 4 mutations (D68X [L69fsX11], C104R, A181E, R202H) have been shown to be statistically significant in common variable immunodeficiency (CVID) and selective IgA deficiency (sIgAD) patients when compared to controls.(4) In addition, several other mutations have been reported but none of these appear to be statistically significant when compared to controls.(4) Two other mutations, P251L and V220A, are considered to be rare polymorphisms as they are present in both controls and patients.(4-6) The TACI gene mutations described so far are nonsense, missense, or frameshift (due to the insertion of a single extra nucleotide) mutations, all of which can be detected by gene sequencing. No large deletions or duplications have been reported for this gene at this time.
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 remain unknown, a fraction of CVID cases (approximately 20%-25%) have been reported to be associated with mutations in the TACI gene, ICOS, BAFF-R, or CD19. Most cases of CID 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 mutations can be inherited in either an autosomal dominant or autosomal recessive fashion. There also appears to be variable penetrance in the familial TACI gene mutations.(7) TACI gene mutations appear to be strongly associated with lymphoproliferative diseases such as splenomegaly or tonsillar hypertrophy. Autoimmune thyroiditis is observed in 15% of TACI gene mutation-positive CVID cases. The incomplete penetrance seen for TACI gene mutations indicates that a mutation can be present, but the individual does not develop the disease phenotype.
The known TACI gene mutations 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 IABCS / B-Cell Phenotyping Profile for Immunodeficiency and Immune Competence Assessment, Blood).(7) In <5% of TACI-associated CVID cases, protein expression on B cells is absent, which can be detected by flow cytometry. Therefore, in the presence of a strong clinical indication for CVID and potential TACI gene mutations, 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 mutations 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 mutations for correlation with clinical phenotype and genetic counseling (TACIG / Transmembrane Activator and CAML Interactor Gene [TACI], Known Mutation Analysis).
An interpretive report will be provided.
An interpretive report is provided that describes the mutations, if any, their potential clinical significance, and whether they have been previously reported or are new mutations. Variants of unknown clinical significance also will be documented in the report.
The published mutations in the TACI gene are a combination of missense, nonsense, small insertion or deletion, and other point mutations, all of which will be detected by full gene sequencing.
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 mutation.
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.
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. Scharenberg AM, Hannibal MC, Torgerson T, et al: Common variable immunodeficiency overview. Gene Reviews 2006, Posted July 5, 2006