Immunodeficiency Disorder CVID Caused by Gene Mutation

Another 35 people with CVID were tested for the gene mutation, and one other unrelated person was found to have it. His father was not tested, but no one else in his family immediate family had the mutation, so the scientists do not know whether he could have inherited the disorder from his father or developed the gene mutation sporadically.

Blood samples were obtained from individuals with CVID, healthy family members, and healthy control subjects. Determination of lymphocyte subpopulations and immunoglobulin levels was carried out via standard laboratory techniques, including flow cytometry and nephelometry. Toll-like receptor (TLR) functional assays with ligands to TLR1–TLR8 were performed on peripheral blood mononuclear cells with supernatant measurement of interleukin-1β (IL-1β), tumor necrosis factor-alpha (TNF-α), and IL-6 production measured by Luminex multianalyte technology at the ARUP Laboratories (Salt Lake City, UT, USA). Cortisol and adrenocorticotropic hormone (ACTH) levels were measured by standard assays for clinical analysis.


The investigators performed exome sequencing in the two families and used bioinformatics approaches, including the Variant Annotation, Analysis and Search Tool (VAAST) algorithm developed at the University, to rapidly identify gene mutations that can cause disease. VAAST identified the nuclear factor of kappa light polypeptide gene enhancer in B-cells 2 (NFKB2) gene. NFKB2 mutation was present in mother and her two affected children and in the patient in the second family. Sequencing of the NFKB2 gene in the 34 other CVID patients did not reveal any other NFKB2 mutations. The team discovered that a mutation in NFKB2 impairs a protein from functioning properly, which interferes with the body's ability to make antibodies and fight infection. The children's father did not have the mutation, nor did a third sibling or the woman's parents.

Karl V. Voelkerding, MD, a professor of pathology and senior author of the study said, “We know the NFKB2 mutations caused the disease in the four patients in this study, but it's difficult to predict how common NFKB2 mutations will ultimately be in other CVID cases.” CVID probably is underdiagnosed, making it hard to know how common it is. But the disorder is estimated to occur in 1 in 10,000 people to 1 in 50,000 people, meaning it is one of more common types of immunodeficiency disorders. The study was published on October 17, 2013, in the American Journal of Human Genetics.

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