See discussions, stats, and author profiles for this publication at: https://www.researchgate.net/publication/303747377 Genes associated with common variable immunodeficiency: one diagnosis to rule them all? Article in Journal of Medical Genetics · June 2016 Impact Factor: 6.34 · DOI: 10.1136/jmedgenet-2015-103690 READS 80 6 authors, including: Melissa Dullaers Bart N Lambrecht Ghent University Ghent University 49 PUBLICATIONS 1,114 CITATIONS 278 PUBLICATIONS 15,377 CITATIONS SEE PROFILE SEE PROFILE Elfride De Baere Filomeen Haerynck Ghent University Ghent University 159 PUBLICATIONS 3,452 CITATIONS 60 PUBLICATIONS 629 CITATIONS SEE PROFILE SEE PROFILE All in-text references underlined in blue are linked to publications on ResearchGate, Available from: Melissa Dullaers letting you access and read them immediately. Retrieved on: 14 June 2016 Downloaded from http://jmg.bmj.com/ on June 5, 2016 - Published by group.bmj.com JMG Online First, published on June 1, 2016 as 10.1136/jmedgenet-2015-103690 Review 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 Haerynck1,2 1Clinical Immunology Research ABSTRACT dominant inheritance.2 So far, a monogenic cause Lab, Department of Pulmonary Common variable immunodeficiency (CVID) is a primary has been identified in 2–10% of patients with Medicine, Ghent University fi 24 Hospital, Ghent, Belgium antibody de ciency characterised by CVID. The majority of these genetic subtypes 2Department of Pediatric hypogammaglobulinaemia, impaired production of are very rare (figure 1 and table 1). The first CVID Immunology and Pulmonology, specific antibodies after immunisation and increased disease genes were discovered using a candidate Centre for Primary susceptibility to infections. CVID shows a considerable gene approach based on single-gene knockout fi – Immunode ciency, Jeffrey phenotypical and genetic heterogeneity. In contrast to mice.5 8 This might explain why many genetic Modell Diagnosis and Research fi Centre, Ghent University many other primary immunode ciencies, monogenic defects described thus far are autosomal recessive. Hospital, Ghent, Belgium forms count for only 2–10% of patients with CVID. The past 4 years, next-generation sequencing 3Center for Medical Genetics, Genes that have been implicated in monogenic CVID (NGS) technologies have accelerated the discovery Ghent University and Ghent include ICOS, TNFRSF13B (TACI), TNFRSF13C (BAFF-R), of both autosomal recessive and dominant CVID University Hospital, Ghent, Belgium TNFSF12 (TWEAK), CD19, CD81, CR2 (CD21), MS4A1 disease genes. In addition, it has become clear that 4Laboratory of (CD20), TNFRSF7 (CD27), IL21, IL21R, LRBA, CTLA4, the clinical diagnosis of CVID is an umbrella cover- Immunoregulation, VIB PRKCD, PLCG2, NFKB1, NFKB2, PIK3CD, PIK3R1, VAV1, ing several genetic subtypes. In fact, many genes Inflammation Research Center, RAC2, BLK, IKZF1 (IKAROS) and IRF2BP2. With the initially reported as CVID disease genes are now Ghent, Belgium increasing number of disease genes identified in CVID, it considered to be responsible for distinct disease 5Department of Internal Medicine, Ghent University, has become clear that CVID is an umbrella diagnosis entities (table 1). Moreover, it has been recently Ghent, Belgium and that many of these genetic defects cause distinct suggested that, apart from rare monogenic forms, 6Tumor Immunology disease entities. Moreover, there is accumulating CVID is a complex rather than a Mendelian Laboratory, Department of evidence that at least a subgroup of patients with CVID disease.249 Pulmonary Medicine, Ghent University Hospital, Ghent, has a complex rather than a monogenic inheritance. This This review outlines current knowledge on the Belgium review aims to discuss current knowledge regarding the molecular basis of CVID, covering both monogenic molecular genetic basis of CVID with an emphasis on and complex forms, and linking with clinical and Correspondence to the relationship with the clinical and immunological immunological phenotypes. Dr Filomeen Haerynck, Princess phenotype. Elisabeth Children’s Hospital, 3K12D, Ghent University GENES ASSOCIATED WITH MONOGENIC Hospital, De Pintelaan 185, FORMS OF CVID Ghent 9000, Belgium; INTRODUCTION Genes encoding receptors and ligands [email protected] Common variable immunodeficiency (CVID) is one ICOS deficiency fi Received 10 February 2016 of the most prevalent primary immunode ciencies Inducible T cell costimulator (ICOS) is a T cell Revised 7 May 2016 (PIDs) with an important morbidity and high surface receptor that belongs to the CD28/CTLA-4 Accepted 10 May 2016 number of medical encounters.12According to the (cytotoxic T lymphocyte-associated antigen 4) international consensus statement, CVID is defined family (figure 2).5 Reciprocal ICOS–ICOS ligand by a marked decrease in serum IgG, decreased IgM interactions are essential for germinal centre (GC) and/or IgA, poor antibody responses to vaccines, formation and terminal B cell differentiation, and exclusion of defined causes of hypogammaglo- effector T cell responses and immune tolerance.5 bulinaemia.2 Its prevalence is estimated between ICOS was the first disease gene identified for 1/10 000 and 1/50 000 in Caucasians; it is rarely monogenic forms of CVID, using a candidate gene described in Asian and African populations.23Age approach based on prior evidence from single-gene of onset is variable, with a peak incidence in child- knockout mice.5 Hitherto, biallelic ICOS mutations hood and in the second and third decades of resulting in complete loss of protein expression – life.23Although patients with CVID share many have been reported in seven families.51013 clinical and immunological features, the degree and Haplotype analysis in the four German/Austrian severity of the presenting phenotype varies consid- families segregating an identical ICOS mutation erably between affected individuals.2 The most con- was indicative for a common founder.10 14 sistent clinical feature is increased susceptibility to ICOS-deficient patients had a variable phenotype (respiratory tract) infections. Patients may also with variable age of onset and severity (table 1).5 – develop complications related to disrupted immune 10 13 Patients commonly presented recurrent homoeostasis such as autoimmunity.2 Besides respiratory tract infections and autoimmune compli- – To cite: Bogaert DJA, impaired Ig production by B cells, abnormalities in cations.51013 Patients with two novel ICOS muta- Dullaers M, Lambrecht BN, almost all components of the immune system have tions published in 2015 extended the clinical et al. J Med Genet Published 2 fl Online First: [please include been described in CVID. spectrum: early onset in ammatory bowel disease, Day Month Year] The majority of CVID cases occur sporadically.2 hepatomegaly with raised liver enzymes, cyto- doi:10.1136/jmedgenet- About 5–25% of patients have a positive family megalovirus viraemia and Pneumocystis jirovecii 2015-103690 history, of which most demonstrate an autosomal 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 Copyright Article author (or their employer) 2016. Produced by BMJ Publishing Group Ltd under licence. Downloaded from http://jmg.bmj.com/ on June 5, 2016 - Published by group.bmj.com Review Figure 1 Estimated share of each disease gene within the common variable immunodeficiency population based on published cases. patient resolved after haematopoietic stem cell transplantation Variants in the genes encoding TACI and BAFF-R have been while diarrhoea persisted in his non-transplanted sister. This indi- identified in patients with CVID by means of a candidate gene – cates that inflammatory gut complications are disease-intrinsic.12 approach based on single-gene knockout mice.6 8 Although ini- Noteworthy, decreased ICOS expression was previously reported tially thought to be fully penetrant, it is currently believed that in an adult Caucasian man with Crohn’s-like colitis and panhypo- monoallelic TNFRSF13B and monoallelic and biallelic gammaglobulinaemia.15 Unfortunately, no mutation analysis of TNFRSF13C variants are by themselves not sufficient to cause a – ICOS was performed.15 CVID phenotype.18 22 All ICOS-deficient patients had very low to absent memory B cells and some also showed a loss of bone marrow plasma TNFRSF13B (encoding TACI) variants 510–14 cells. This might be due to defective GC reactions in the Biallelic and monoallelic loss-of-function variants in 14 fi absence of ICOS signalling. ICOS-de cient patients also TNFRSF13B have been registered in at least 2147 patients based demonstrated varying degrees of T cell defects (table 1). In con- on the Jeffrey Modell Centers Global Network report.1 Biallelic fi trast to the rst-reported German/Austrian families, the TNFRSF13B variants have always been associated with some – Japanese, Kuwaiti and Pakistani sibling pairs demonstrated pro- degree of antibody deficiency,6 7 19 20 23 27 except for a homo- nounced T cell defects with viral and opportunistic infections zygous C104R variant in a 25-year-old member of a fi resembling combined immunode ciency (CID) rather than CVID-affected family who was asymptomatic and had normal 510–14 CVID. Therefore, ICOS mutations are no longer consid- Ig levels at the time of the study.24 The latter individual could ered to cause a pure CVID phenotype