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

• Published in: Journal of allergy and clinical immunology Vol. 138; no. 2; pp. 544 - 550.e4
• Main Authors: Keller, Michael D., Pandey, Rahul, Li, Dong, Glessner, Joseph, Tian, Lifeng, Henrickson, Sarah E., Chinn, Ivan K., Monaco-Shawver, Linda, Heimall, Jennifer, Hou, Cuiping, Otieno, Frederick G., Jyonouchi, Soma, Calabrese, Leonard, van Montfrans, Joris, Orange, Jordan S., Hakonarson, Hakon
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.08.2016; Elsevier Limited
• Subjects: Adolescent; Adult; Aged; Algorithms; Allergy and Immunology; B-Lymphocyte Subsets - immunology; B-Lymphocyte Subsets - metabolism; Biomarkers; Carrier Proteins - genetics; Carrier Proteins - metabolism; Cell Differentiation - genetics; Cell Differentiation - immunology; Classification; Common variable immunodeficiency; Common Variable Immunodeficiency - diagnosis; Common Variable Immunodeficiency - genetics; Common Variable Immunodeficiency - immunology; Deoxyribonucleic acid; DNA; Epstein-Barr virus; Exome; Family; Female; Flow cytometry; Genes; Genetic Association Studies; Genetic Predisposition to Disease; Genetic testing; Genotype; High-Throughput Nucleotide Sequencing; Humans; immunoglobulin; Immunoglobulin Isotypes - blood; Immunoglobulin Isotypes - immunology; Immunoglobulins; Immunophenotyping; IRF2BP2; Lymphocytes; machine learning; Male; Middle Aged; Mutation; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Patients; Pedigree; Phenotype; primary antibody deficiency; Studies; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - metabolism; Young Adult; CVID; Common variable immunodeficiency; primary antibody deficiency; immunoglobulin; SNP; IRF2BP2; CNV; SVM; machine learning; EBV-LCL; EBV-immortalized lymphoblastoid cell line; Support vector machine; Copy number variation; Common variable immunodeficiency disorder; Single nucleotide polymorphism
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2016.01.018

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