Disease

LRBA Deficiency

Description

Common variable immunodeficiency (CVID) is the most common primary immunodeficiency and antibody deficiency. It is a clinically and genetically heterogeneous group of disorders caused by a defect in B cell differentiation and impaired immunoglobulin secretion. CVID is characterized by normal or low circulating B cell, antibody deficiency, hypogammaglobulinemia and recurrent bacterial infections (Jolles et al. 2013). Mutations in LRBA are associated with CVID type 8, or LRBA deficiency, an autosomal recessive condition characterized by respiratory infections and autoimmune disorders such as idiopathic thrombocytopenic purpura, autoimmune hemolytic anemia, and inflammatory bowel disease (Alangari et al. 2012; Lopez-Herrera et al. 2012).

The LRBA gene encodes the lipopolysaccharide-responsive vesicle trafficking, beach- and anchor-containing protein, which is found in the cytosol and expressed in many tissues. This protein is involved in regulating recycling of the cytotoxic T lymphocyte-associated protein 4 (CTLA4), which is found in intracellular compartments and regulates autoimmune responses in the body (Lo et al. 2015). Deficient protein expression has been reported to lead to defects in B and T-cell activation along with a decreased sensitivity to apoptosis.

Indications

Confirmation of diagnosis in a patient with the following:

  • Combined immunodeficiency or combined variable immunodeficiency (CVID)
  • Early-onset colitis with autoimmunity
  • Family member with previously identified LRBA mutation(s)

Testing Methodology

Testing is performed by Sanger sequencing of the entire coding regions and intron/exon boundaries of the LRBA gene. 

Test Sensitivity

Clinical Sensitivity

The clinical sensitivity of sequencing is unknown, as only six mutations have been reported in this gene.

Analytical Sensitivity

The sensitivity of DNA sequencing is over 99% for the detection of nucleotide base changes, small deletions and insertions in the regions analyzed.

Mutations in regulatory regions or other untranslated regions are not detected by this test. Large deletions involving entire single exons or multiple exons, large insertions and other complex genetic events have been reported in many of these genes and will not be identified using this test methodology. Rare primer site variants may lead to erroneous results.

Turnaround Time

42 days

References

Alangari, A., A. Alsultan, et al. (2012) "LPS-Responsive Beige-like Anchor (LRBA) Gene Mutation in a Family with Inflammatory Bowel Disease and Combined Immunodeficiency." J Allergy Clin Immunol 130(2): 481–8 e2.

Jolles, S. (2013) "The Variable in Common Variable Immunodeficiency: A Disease of Complex Phenotypes." The Journal of Allergy and Clinical Immunology. In Practice 1(6): 545–56.

Lo, B., K. Zhang, et al. (2015) "AUTOIMMUNE DISEASE. Patients with LRBA Deficiency Show CTLA4 Loss and Immune Dysregulation Responsive to Abatacept Therapy." Science (New York, N.Y.) 349(6246): 436–40.

Lopez-Herrera, G., G. Tampella, et al. (2012) "Deleterious Mutations in LRBA Are Associated with a Syndrome of Immune Deficiency and Autoimmunity." American Journal of Human Genetics 90(6): 986–1001.

Wang, J.-W., J.J. Gamsby, et al. (2004) "Deregulated Expression of LRBA Facilitates Cancer Cell Growth." Oncogene 23(23): 4089–97.