UGP investigators discover a new genetic cause for a hard-to-diagnose immunodeficiency disease

In November 2013, Utah Genome Project (UGP) investigators published their discovery of a new genetic cause for common variable immune disease—CVID for short—one of the more common types of immunodeficiency disorders, affecting about 1 in 25,000 people. People with CVID have lower than normal levels of infection-fighting antibodies, so they experience frequent upper respiratory infections. They are also prone to develop additional, serious complications including autoimmune disorders and lymphomas. A few genes had previously been implicated in about one-tenth of CVID cases, leaving the genetic underpinnings of most cases an open question.

This open genetic question attracted an interdisciplinary team of physicians and geneticists from the University of Utah School of Medicine Departments of Pediatrics, Pathology, and Human Genetics, the Program in Molecular Medicine, and ARUP, the University-owned, nationwide testing laboratory. Physicians Karin Chen, M.D., instructor of pediatric immunology, John F. Bohnsack, M.D., professor of pediatrics, and Harry R. Hill, M.D., professor of pathology, care for many of the CVID patients in the Intermountain Region. Their close connections with patients have provided unique opportunities to study the genetics of CVID. The key to the recent CVID discovery, as with all Utah Genome Project discoveries, was an affected family willing to participate in research.

The first member of the family to be diagnosed with CVID was a young boy (age three at diagnosis) who had recurring lung, sinus and ear infections. The boy’s mother and sister, who also had histories of upper respiratory infections, were then diagnosed. The three affected family members and four unaffected members contributed their DNA for sequencing and analysis. Using rapid sequencing and a powerful genetic search engine (VAAST) developed at the U, Karl V. Voelkerding, M.D., U professor of pathology and medical director for genomics and bioinformatics at ARUP, and Lynn Jorde, U professor and chair of human genetics, led an elite team of geneticists in identifying a novel—or not previously identified—mutation in a gene called NFKB2.

The NFKB2 gene, which encodes a protein involved in immune cell function, had never before been implicated in a human immunodeficiency disorder. This discovery gives scientists a new window into the molecular mechanisms of CVID. This new knowledge may lead to better therapies than the currently prescribed treatment of monthly antibody infusions, which cost up to $10,000 per treatment. An immediate benefit of the NFKB2 discovery is a diagnostic test for this form of CVID, which ARUP plans to release in 2014. A diagnostic test for CVID will mean earlier diagnosis and earlier treatment, ultimately preventing damage to the lungs and other organs and preserving overall health in individuals living with CVID.

Read the press release here.

*K. Chen, E. M. Coonrod, A. Kumánovics, Z.F. Franks, J.D. Durtschi, et al. Germline mutations in NFKB2 implicate the noncanonical NF-κB pathway in the pathogenesis of common variable immunodeficiency. American Journal of Human Genetics, 93(5), 812-824 (November 2013)

About the Author:

Amy DavisDirector, Research Program Development, Utah Genome Project.