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NFKB1 and CVID: the most frequent monogenic cause in a complex disease

Published online: February 23, 2018

Common Variable Immunodeficiency (CVID) is the most frequent immunodeficiency, characterized by recurrent (respiratory) infections and low levels of antibody. Additionally, a proportion of these patients suffer from autoimmunity, autoinflammation, and/or malignancy. CVID is often considered to be a complex and multifactorial disorder, however, family studies suggest that the disease can be inherited and caused by single gene mutations in at least 10% of cases.

Rather than the traditional approach of genetic investigations in individual families, Tuijnenburg and colleagues sequenced the genomes of a large number of unrelated CVID patients, as part of the UK NIHR BioResource – Rare Disease project. By comparing the DNA sequences of 390 CVID patients to those of 7,000 individuals without an immune deficiency (controls) they found that 1 in 25 of the CVID cohort, had one of 16 uncommon variants in the NFKB1 gene. The researchers collected blood samples of affected patients and performed pedigree analysis to investigate how these variants might cause CVID.   Pedigree analysis suggested a penetrance of about 60%.  Truncating and missense variants, and gene deletion were associated with reduced NF-kappa-B protein expression. The patients’ B cells showed a severe reduction in normal memory B cells, and the investigators demonstrate how the presence of an increased (CD21low) B cell population correlates with development of disease in individuals carrying these variants.

This study has revealed that mutations in the NFKB1 gene are the most common monogenic cause of CVID. The authors highlight that if an NFKB1 mutation is identified in a patient, other relatives, including those who are still asymptomatic, should have the genetic test so that mutation carriers can be closely monitored for disease development.

The Journal of Allergy and Clinical Immunology (JACI) is an official scientific journal of the AAAAI and is the most-cited journal in the field of allergy and clinical immunology.