Mutation in IRF2BP2 is responsible for a familial form of common variable immunodeficiency disorder

J Allergy Clin Immunol. 2016 Aug;138(2):544-550.e4. doi: 10.1016/j.jaci.2016.01.018. Epub 2016 Mar 23.


Background: Genome-wide association studies have shown a pattern of rare copy number variations and single nucleotide polymorphisms in patients with common variable immunodeficiency disorder (CVID), which was recognizable by a support vector machine (SVM) algorithm. However, rare monogenic causes of CVID might lack such a genetic fingerprint.

Objective: We sought to identify a unique monogenic cause of familial immunodeficiency and evaluate the use of SVM to identify patients with possible monogenic disorders.

Methods: A family with multiple members with a diagnosis of CVID was screened by using whole-exome sequencing. The proband and other subjects with mutations associated with CVID-like phenotypes were screened through the SVM algorithm from our recent CVID genome-wide association study. RT-PCR, protein immunoblots, and in vitro plasmablast differentiation assays were performed on patient and control EBV lymphoblastoids cell lines.

Results: Exome sequencing identified a novel heterozygous mutation in IRF2BP2 (c.1652G>A:p.[S551N]) in affected family members. Transduction of the mutant gene into control human B cells decreased production of plasmablasts in vitro, and IRF2BP2 transcripts and protein expression were increased in proband versus control EBV-immortalized lymphoblastoid cell lines. The SVM algorithm categorized the proband and subjects with other immunodeficiency-associated gene variants in TACI, BAFFR, ICOS, CD21, LRBA, and CD27 as genetically dissimilar from polygenic CVID.

Conclusion: A novel IRFBP2 mutation was identified in a family with autosomal dominant CVID. Transduction experiments suggest that the mutant protein has an effect on B-cell differentiation and is likely a monogenic cause of the family's CVID phenotype. Successful grouping by the SVM algorithm suggests that our family and other subjects with rare immunodeficiency disorders cluster separately and lack the genetic pattern present in polygenic CVID cases.

Keywords: Common variable immunodeficiency; IRF2BP2; immunoglobulin; machine learning; primary antibody deficiency.

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • B-Lymphocyte Subsets / immunology
  • B-Lymphocyte Subsets / metabolism
  • Biomarkers
  • Carrier Proteins / genetics*
  • Carrier Proteins / metabolism
  • Cell Differentiation / genetics
  • Cell Differentiation / immunology
  • Common Variable Immunodeficiency / diagnosis
  • Common Variable Immunodeficiency / genetics*
  • Common Variable Immunodeficiency / immunology*
  • DNA-Binding Proteins
  • Exome
  • Family
  • Female
  • Genetic Association Studies
  • Genetic Predisposition to Disease*
  • Genotype
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Immunoglobulin Isotypes / blood
  • Immunoglobulin Isotypes / immunology
  • Immunophenotyping
  • Male
  • Middle Aged
  • Mutation*
  • Nuclear Proteins / genetics*
  • Nuclear Proteins / metabolism
  • Pedigree
  • Phenotype
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / metabolism
  • Transcription Factors
  • Young Adult


  • Biomarkers
  • Carrier Proteins
  • DNA-Binding Proteins
  • IRF2BP2 protein, human
  • Immunoglobulin Isotypes
  • Nuclear Proteins
  • Transcription Factors