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

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/88800 B-Cell Phenotyping Profile for Immunodeficiency and Immune Competence Assessment, Blood).

• Informed Consent for Genetic Testing
• TACI Genotyping Patient Information Sheet
• Multiple Whole Blood EDTA Genotype Tests

Polymerase Chain Reaction (PCR) Followed by DNA Sequence Analysis

(PCR is utilized pursuant to a license agreement with Roche Molecular Systems, Inc.)

Multiple whole blood EDTA genotype tests can be performed on a single specimen after a single extraction. See Multiple Whole Blood EDTA Genotype Tests in Special Instructions for a list of tests that can be ordered together.

Container/Tube: Lavender top (EDTA)       

Specimen Volume: 3 mL

Collection Instructions: Send specimen in original tube.

Additional Information:                                                

1. Ordering physician's name and phone number are required.

2. Bone marrow transplants will interfere with testing. Call Mayo Medical Laboratories at 800-533-1710 or 507-266-5700 for instructions.

3. Transfusions will interfere with testing for up to 4 to 6 weeks. DNA obtained from white cells may not provide useful information for patients who received a recent transfusion of blood that was not leukocyte-reduced. Wait 4 to 6 weeks until transfused cells have left the patient's circulation before drawing the patient's blood specimen for genotype testing.

Forms:

1. TACI Genotyping Patient Information Sheet (Supply T604) in Special Instructions.

2. New York Clients-Informed consent is required. Please document on the request form or electronic order that a copy is on file. An Informed Consent for Genetic Testing (Supply T576) is available in Special Instructions.

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 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 TAC, 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 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 mutations can be inherited in either an autosomal dominant or autosomal recessive fashion. There also appears to be variable penetrance in the familial TACI mutations. (7) TACI mutations appear to be strongly associated with lymphoproliferative diseases such as splenomegaly or tonsillar hypertrophy. Autoimmune thyroiditis is observed in 15% of TACI mutation-positive CVID cases. The incomplete penetrance seen for TACI mutations indicates that a mutation can be present, but the individual does not develop the disease phenotype.

The known TACI 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/88800 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 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 mutations for correlation with clinical phenotype and genetic counseling (TACIG/89122 Transmembrane Activator and CAML Interactor Gene [TACI], Known Mutation Analysis).

An interpretive report will be provided.

An interpretive report is provided that describes the mutation(s), 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.

Only symptomatic individuals should be tested. This test should not be used for screening asymptomatic family members of patients who have a documented TACI 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 http://www.genetests.org/profiles/cvid

Genomic DNA is first extracted from the whole blood, followed by TACI gene amplification by PCR. The PCR product is then separated from unincorporated primers, nucleotides and contaminants by column purification, then sequenced in both directions using sequencing primers and fluorescent dye-terminator chemistry. Sequencing products are separated on an automated sequencer and trace files are analyzed for variations in the exons and intron/exon boundaries of all 5 exons using specialized mutation detection software and visual inspection.(Unpublished Mayo method)

Wednesday

81479 -Unlisted molecular pathology procedure