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Identifying the presence of a TACI gene mutation in a symptomatic patient when the mutation has been identified in an affected family member
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.(1) TACI regulates isotype class-switching of immunoglobulins and also is involved in the antibody response to T-independent antigens.(2)
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.(2) 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. Six mutations (D68X [also called L69fsX11], C104R, S144X, A181E, S194X, and R202H) were identified in the TACI gene in the original reports.(3,4) Of these 6 mutations, 4 (D68X, C104R, A181E, and R202H) have been shown to be statistically significant in common variable immunodeficiency (CVID) and selective IgA deficiency (sIgAD) patients, when compared to controls.(5) Several other mutations have been reported, but none of these appear to be statistically significant when compared to controls.(5) Two other mutations, P251L and V220A, are considered to be rare polymorphisms as they are present in both controls and patients.(3-5) 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.
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 and require gene sequencing analysis to confirm the presence of the mutation as well as correlation with the clinical phenotype.
An interpretive report will be provided.
An interpretive report will be provided that describes the presence or absence of the previously identified mutations, and their potential clinical significance. Variants of unknown clinical significance within the specific exon being evaluated also will be documented in the report.
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.
This test will only determine if the specific mutation previously described in a family member is present or not.
Only symptomatic family members of an affected patient, in whom a mutation has been identified, should be tested with this assay.
1. Mackay F, Ambrose C: The TNF family members BAFF and APRIL: the growing complexity. Cytokine Growth Factor Rev 2003;14:311-324
2. Castigli E, Geha RS: Molecular basis of common variable immunodeficiency. J Allergy Clin Immunol 2006;117:740-746
3. 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
4. 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
5. 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