Genes associated with common variable immunodeficiency: one diagnosis to rule them all? Delfien J A Bogaert, 1,2,3,4 Melissa Dullaers, 1,4,5 Bart N Lambrecht, 4,5 Karim Y Vermaelen, 1,5,6 Elfride De Baere, 3 Filomeen Haerynck 1,2 1 Clinical Immunology Research Lab, Department of Pulmonary Medicine, Ghent University Hospital, Ghent, Belgium 2 Department of Pediatric Immunology and Pulmonology, Centre for Primary Immunodeficiency, Jeffrey Modell Diagnosis and Research Centre, Ghent University Hospital, Ghent, Belgium 3 Center for Medical Genetics, Ghent University and Ghent University Hospital, Ghent, Belgium 4 Laboratory of Immunoregulation, VIB Inflammation Research Center, Ghent, Belgium 5 Department of Internal Medicine, Ghent University, Ghent, Belgium 6 Tumor Immunology Laboratory, Department of Pulmonary Medicine, Ghent University Hospital, Ghent, Belgium Correspondence to Dr Filomeen Haerynck, Princess Elisabeth Children’s Hospital, 3K12D, Ghent University Hospital, De Pintelaan 185, Ghent 9000, Belgium; Filomeen.Haerynck@uzgent.be Received 10 February 2016 Revised 7 May 2016 Accepted 10 May 2016 To cite: Bogaert DJA, Dullaers M, Lambrecht BN, et al. J Med Genet Published Online First: [ please include Day Month Year] doi:10.1136/jmedgenet- 2015-103690 ABSTRACT Common variable immunodeficiency (CVID) is a primary antibody deficiency characterised by hypogammaglobulinaemia, impaired production of specific antibodies after immunisation and increased susceptibility to infections. CVID shows a considerable phenotypical and genetic heterogeneity. In contrast to many other primary immunodeficiencies, monogenic forms count for only 2–10% of patients with CVID. Genes that have been implicated in monogenic CVID include ICOS, TNFRSF13B (TACI), TNFRSF13C (BAFF-R), TNFSF12 (TWEAK), CD19, CD81, CR2 (CD21), MS4A1 (CD20), TNFRSF7 (CD27), IL21, IL21R, LRBA, CTLA4, PRKCD, PLCG2, NFKB1, NFKB2, PIK3CD, PIK3R1, VAV1, RAC2, BLK, IKZF1 (IKAROS) and IRF2BP2. With the increasing number of disease genes identified in CVID, it has become clear that CVID is an umbrella diagnosis and that many of these genetic defects cause distinct disease entities. Moreover, there is accumulating evidence that at least a subgroup of patients with CVID has a complex rather than a monogenic inheritance. This review aims to discuss current knowledge regarding the molecular genetic basis of CVID with an emphasis on the relationship with the clinical and immunological phenotype. INTRODUCTION Common variable immunodeficiency (CVID) is one of the most prevalent primary immunodeficiencies (PIDs) with an important morbidity and high number of medical encounters. 12 According to the international consensus statement, CVID is defined by a marked decrease in serum IgG, decreased IgM and/or IgA, poor antibody responses to vaccines, and exclusion of defined causes of hypogammaglo- bulinaemia. 2 Its prevalence is estimated between 1/10 000 and 1/50 000 in Caucasians; it is rarely described in Asian and African populations. 23 Age of onset is variable, with a peak incidence in child- hood and in the second and third decades of life. 2 3 Although patients with CVID share many clinical and immunological features, the degree and severity of the presenting phenotype varies consid- erably between affected individuals. 2 The most con- sistent clinical feature is increased susceptibility to (respiratory tract) infections. Patients may also develop complications related to disrupted immune homoeostasis such as autoimmunity. 2 Besides impaired Ig production by B cells, abnormalities in almost all components of the immune system have been described in CVID. 2 The majority of CVID cases occur sporadically. 2 About 5–25% of patients have a positive family history, of which most demonstrate an autosomal dominant inheritance. 2 So far, a monogenic cause has been identified in 2–10% of patients with CVID. 2 4 The majority of these genetic subtypes are very rare ( figure 1 and table 1). The first CVID disease genes were discovered using a candidate gene approach based on single-gene knockout mice. 5–8 This might explain why many genetic defects described thus far are autosomal recessive. The past 4 years, next-generation sequencing (NGS) technologies have accelerated the discovery of both autosomal recessive and dominant CVID disease genes. In addition, it has become clear that the clinical diagnosis of CVID is an umbrella cover- ing several genetic subtypes. In fact, many genes initially reported as CVID disease genes are now considered to be responsible for distinct disease entities (table 1). Moreover, it has been recently suggested that, apart from rare monogenic forms, CVID is a complex rather than a Mendelian disease. 249 This review outlines current knowledge on the molecular basis of CVID, covering both monogenic and complex forms, and linking with clinical and immunological phenotypes. GENES ASSOCIATED WITH MONOGENIC FORMS OF CVID Genes encoding receptors and ligands ICOS deficiency Inducible T cell costimulator (ICOS) is a T cell surface receptor that belongs to the CD28/CTLA-4 (cytotoxic T lymphocyte-associated antigen 4) family ( figure 2). 5 Reciprocal ICOS–ICOS ligand interactions are essential for germinal centre (GC) formation and terminal B cell differentiation, effector T cell responses and immune tolerance. 5 ICOS was the first disease gene identified for monogenic forms of CVID, using a candidate gene approach based on prior evidence from single-gene knockout mice. 5 Hitherto, biallelic ICOS mutations resulting in complete loss of protein expression have been reported in seven families. 5 10–13 Haplotype analysis in the four German/Austrian families segregating an identical ICOS mutation was indicative for a common founder. 10 14 ICOS-deficient patients had a variable phenotype with variable age of onset and severity (table 1). 5 10–13 Patients commonly presented recurrent respiratory tract infections and autoimmune compli- cations. 5 10–13 Patients with two novel ICOS muta- tions published in 2015 extended the clinical spectrum: early onset inflammatory bowel disease, hepatomegaly with raised liver enzymes, cyto- megalovirus viraemia and Pneumocystis jirovecii pneumonia. 12 13 Enteropathy in one ICOS-deficient Bogaert DJA, et al. J Med Genet 2016;0:1–16. doi:10.1136/jmedgenet-2015-103690 1 Review JMG Online First, published on June 1, 2016 as 10.1136/jmedgenet-2015-103690 Copyright Article author (or their employer) 2016. Produced by BMJ Publishing Group Ltd under licence. group.bmj.com on June 5, 2016 - Published by http://jmg.bmj.com/ Downloaded from