Molecular Genetics of Common Variable Immunodeficiency

Abstract

Common variable immunodeficiency (CVID) is one of the most frequently diagnosed primary immunodeficiencies (PIDs) characterised by antibody deficiency, poor responses to vaccination and an increased susceptibility to infections and complications due to immune dysregulation. The clinical diagnosis of CVID is an umbrella covering an immunologically and genetically heterogeneous group of diseases. To date, 22 disease‐causing genes have been associated with monogenic forms of CVID, encompassing 2–10% of reported cases. However, these genetic subtypes are now considered to account for distinct disease entities and have been removed from under the CVID umbrella. Furthermore, accumulating data suggest that the majority of CVID patients have a complex or multifactorial disorder, in which multiple genetic, epigenetic and/or environmental factors are involved. Genetic testing for monogenic causes should especially be performed in CVID patients with early onset of disease, noninfectious complications, a positive family history and/or consanguineous parents, since this could be important for genetic counselling, follow up and/or treatment decisions.

Key Concepts

  • CVID is a diagnosis of exclusion, encompassing a clinically, immunologically and genetically heterogeneous group of PID patients.
  • Monogenic defects have so far been reported in 2–10% of CVID patients.
  • The majority of CVID patients are believed to have a complex or multifactorial aetiology.
  • Patients in whom a monogenic cause is identified are no longer classified under CVID, but under separate disease entities (IUIS classification).
  • A monogenic cause of CVID is more probable in case of early onset of disease, complications of immune dysregulation, a positive family history and/or consanguinity.
  • Especially in CVID patients with early onset of disease and/or noninfectious complications, genetic workup should be performed to identify or exclude an underlying monogenic cause since this could be important for patient management decisions.

Keywords: common variable immunodeficiency; primary antibody deficiencies; hypogammaglobulinaemia; genetics; monogenic; multifactorial; complex disease

Figure 1. Estimated proportion of each disease gene within the CVID population based on published cases. Reproduced with permission from Bogaert et al. 2016 © BMJ Publishing Group Limited.
Figure 2. Schematic representation of the proteins encoded by genes (initially) associated with monogenic forms of CVID (red colour). Only the most important interacting molecules, pathways and functions relevant to this article are shown. Reproduced with permission from Bogaert et al. 2016 © BMJ Publishing Group Limited.
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References

Abolhassani H, Wang N, Aghamohammadi A, et al. (2014) A hypomorphic recombination‐activating gene 1 (RAG1) mutation resulting in a phenotype resembling common variable immunodeficiency. The Journal of Allergy and Clinical Immunology 134 (6): 1375–1380.

Abolhassani H, Cheraghi T, Rezaei N, Aghamohammadi A and Hammarstrom L (2015) Common variable immunodeficiency or late‐onset combined immunodeficiency: a new hypomorphic JAK3 patient and review of the literature. Journal of Investigational Allergology & Clinical Immunology 25: 218–220.

Alangari A, Alsultan A, Adly N, et al. (2012) LPS‐responsive beige‐like anchor (LRBA) gene mutation in a family with inflammatory bowel disease and combined immunodeficiency. The Journal of Allergy and Clinical Immunology 130 (2): 481–488.e2.

Alkhairy OK, Rezaei N, Graham RR, et al. (2015) RAC2 loss‐of‐function mutation in 2 siblings with characteristics of common variable immunodeficiency. The Journal of Allergy and Clinical Immunology 135 (5): 1380–1384.e1‐5.

Alkuraya FS (2010) Homozygosity mapping: one more tool in the clinical geneticist's toolbox. Genetics in Medicine 12 (4): 236–239.

Alkuraya FS (2013) The application of next‐generation sequencing in the autozygosity mapping of human recessive diseases. Human Genetics 32 (11): 1197–1211.

Angulo I, Vadas O, Garcon F, et al. (2013) Phosphoinositide 3‐kinase delta gene mutation predisposes to respiratory infection and airway damage. Science (New York, N.Y.) 342 (6160): 866–871.

Bellacchio E, Palma A, Corrente S, et al. (2014) The possible implication of the S250C variant of the autoimmune regulator protein in a patient with autoimmunity and immunodeficiency: in silico analysis suggests a molecular pathogenic mechanism for the variant. Gene 549 (2): 286–294.

Bogaert DJ, Dullaers M, Lambrecht BN, et al. (2016) Genes associated with common variable immunodeficiency: one diagnosis to rule them all? Journal of Medical Genetics 53 (9): 575–590.

Bogaert DJ, De Bruyne M, Debacker V, et al. (2017a) The immunophenotypic fingerprint of patients with primary antibody deficiencies is partially present in their asymptomatic first‐degree relatives. Haematologica 102 (1): 192–202.

Bogaert DJ, Dullaers M, Kuehn HS, et al. (2017b) Early‐onset primary antibody deficiency resembling common variable immunodeficiency challenges the diagnosis of Wiedeman‐Steiner and Roifman syndromes. Scientific Reports 7 (1): 3702.

Bonilla FA, Barlan I, Chapel H, et al. (2016) International Consensus Document (ICON): common variable immunodeficiency disorders. The Journal of Allergy and Clinical Immunology. In Practice 4 (1): 38–59.

Borte S, Celiksoy MH, Menzel V, et al. (2014) Novel NLRP12 mutations associated with intestinal amyloidosis in a patient diagnosed with common variable immunodeficiency. Clinical Immunology 154 (2): 105–111.

Buchbinder D, Baker R, Lee YN, et al. (2015) Identification of patients with RAG mutations previously diagnosed with common variable immunodeficiency disorders. Journal of Clinical Immunology 35 (2): 119–124.

Burns SO, Zenner HL, Plagnol V, et al. (2012) LRBA gene deletion in a patient presenting with autoimmunity without hypogammaglobulinemia. The Journal of Allergy and Clinical Immunology 130 (6): 1428–1432.

Capitani N, Ariani F, Amedei A, et al. (2012) Vav1 haploinsufficiency in a common variable immunodeficiency patient with defective T‐cell function. International Journal of Immunopathology and Pharmacology 25 (3): 811–817.

Castigli E, Wilson SA, Garibyan L, et al. (2005) TACI is mutant in common variable immunodeficiency and IgA deficiency. Nature Genetics 37 (8): 829–834.

Chandra A, Zhang F, Gilmour KC, et al. (2016) Common variable immunodeficiency and natural killer cell lymphopenia caused by Ets‐binding site mutation in the IL‐2 receptor gamma (IL2RG) gene promoter. The Journal of Allergy and Clinical Immunology 137 (3): 940–942.e4.

Chen K, Coonrod EM, Kumanovics A, et al. (2013) Germline mutations in NFKB2 implicate the noncanonical NF‐kappaB pathway in the pathogenesis of common variable immunodeficiency. American Journal of Human Genetics 93 (5): 812–824.

Chou J, Lutskiy M, Tsitsikov E, et al. (2014) Presence of hypogammaglobulinemia and abnormal antibody responses in GATA2 deficiency. The Journal of Allergy and Clinical Immunology 134 (1): 223–226.

Compeer EB, Janssen W, van Royen‐Kerkhof A, et al. (2015) Dysfunctional BLK in common variable immunodeficiency perturbs B‐cell proliferation and ability to elicit antigen‐specific CD4+ T‐cell help. Oncotarget 6 (13): 10759–10771.

Conley ME and Casanova JL (2014) Discovery of single‐gene inborn errors of immunity by next generation sequencing. Current Opinion in Immunology 30: 17–23.

Coulter TI, Chandra A, Bacon CM, et al. (2017) Clinical spectrum and features of activated phosphoinositide 3‐kinase delta syndrome: a large patient cohort study. The Journal of Allergy and Clinical Immunology 139 (2): 597–606.

Deau MC, Heurtier L, Frange P, et al. (2014) A human immunodeficiency caused by mutations in the PIK3R1 gene. The Journal of Clinical Investigation 124 (9): 3923–3928.

Driessen GJ, IJspeert H, Wentink M, et al. (2016) Increased PI3K/Akt activity and deregulated humoral immune response in human PTEN deficiency. The Journal of Allergy and Clinical Immunology 138 (6): 1744–1747.e5.

Fang M, Abolhassani H, Lim CK, Zhang J and Hammarstrom L (2016) Next generation sequencing data analysis in primary immunodeficiency disorders ‐ Future directions. Journal of Clinical Immunology 36 (Suppl 1): 68–75.

Fliegauf M, Bryant VL, Frede N, et al. (2015) Haploinsufficiency of the NF‐kappaB1 subunit p50 in common variable immunodeficiency. American Journal of Human Genetics 97 (3): 389–403.

Flinsenberg TW, Janssen WJ, Herczenik E, et al. (2014) A novel FcgammaRIIa Q27W gene variant is associated with common variable immune deficiency through defective FcgammaRIIa downstream signaling. Clinical Immunology 155 (1): 108–117.

Goodwin S, McPherson JD and McCombie WR (2016) Coming of age: ten years of next‐generation sequencing technologies. Nature Reviews Genetics 17 (6): 333–351.

Grimbacher B, Hutloff A, Schlesier M, et al. (2003) Homozygous loss of ICOS is associated with adult‐onset common variable immunodeficiency. Nature Immunology 4 (3): 261–268.

Hoshino A, Okada S, Yoshida K, et al. (2016) Abnormal hematopoiesis and autoimmunity in human subjects with germline IKZF1 mutations. Journal of Allergy and Clinical Immunology 140 (1): 223–231.

Kearney HM, Thorland EC, Brown KK, et al. (2011) American College of Medical Genetics standards and guidelines for interpretation and reporting of postnatal constitutional copy number variants. Genetics in Medicine 13 (7): 680–685.

Keller MD, Pandey R, Li D, et al. (2016) Mutation in IRF2BP2 is responsible for a familial form of common variable immunodeficiency disorder. The Journal of Allergy and Clinical Immunology 138 (2): 544–550.e4.

Kobbe R, Kolster M, Fuchs S, et al. (2016) Common variable immunodeficiency, impaired neurological development and reduced numbers of T regulatory cells in a 10‐year‐old boy with a STAT1 gain‐of‐function mutation. Gene 586 (2): 234–238.

Kotlarz D, Zietara N, Uzel G, et al. (2013) Loss‐of‐function mutations in the IL‐21 receptor gene cause a primary immunodeficiency syndrome. The Journal of Experimental Medicine 210 (3): 433–443.

Kuehn HS, Ouyang W, Lo B, et al. (2014) Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science (New York, N.Y.) 345 (6204): 1623–1627.

Kuehn HS, Boisson B, Cunningham‐Rundles C, et al. (2016) Loss of B cells in patients with heterozygous mutations in IKAROS. The New England Journal of Medicine 374 (11): 1032–1043.

Kuijpers TW, Bende RJ, Baars PA, et al. (2010) CD20 deficiency in humans results in impaired T cell‐independent antibody responses. The Journal of Clinical Investigation 120 (1): 214–222.

Li J, Jorgensen SF, Maggadottir SM, et al. (2015) Association of CLEC16A with human common variable immunodeficiency disorder and role in murine B cells. Nature Communications 6: 6804.

Lopez‐Herrera G, Tampella G, Pan‐Hammarstrom Q, et al. (2012) Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity. American Journal of Human Genetics 90 (6): 986–1001.

Lucas CL, Zhang Y, Venida A, et al. (2014) Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K. The Journal of Experimental Medicine 211 (13): 2537–2547.

Lucas CL, Chandra A, Nejentsev S, Condliffe AM and Okkenhaug K (2016) PI3Kdelta and primary immunodeficiencies. Nature Reviews Immunology 16 (11): 702–714.

van Montfrans JM, Hoepelman AI, Otto S, et al. (2012) CD27 deficiency is associated with combined immunodeficiency and persistent symptomatic EBV viremia. The Journal of Allergy and Clinical Immunology 129 (3): 787–793.e6.

Nijman IJ, van Montfrans JM, Hoogstraat M, et al. (2014) Targeted next‐generation sequencing: a novel diagnostic tool for primary immunodeficiencies. The Journal of Allergy and Clinical Immunology 133 (2): 529–534.

Offer SM, Pan‐Hammarstrom Q, Hammarstrom L and Harris RS (2010) Unique DNA repair gene variations and potential associations with the primary antibody deficiency syndromes IgAD and CVID. PLoS One 5 (8): e12260.

Ombrello MJ, Remmers EF, Sun G, et al. (2012) Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions. The New England Journal of Medicine 366 (4): 330–338.

Orange JS, Glessner JT, Resnick E, et al. (2011) Genome‐wide association identifies diverse causes of common variable immunodeficiency. The Journal of Allergy and Clinical Immunology 127 (6): 1360–1367.e6.

Packwood K, Drewe E, Staples E, et al. (2010) NOD2 polymorphisms in clinical phenotypes of common variable immunodeficiency disorders. Clinical and Experimental Immunology 161 (3): 536–541.

Pan‐Hammarstrom Q, Salzer U, Du L, et al. (2007) Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency. Nature Genetics 39 (4): 429–430.

Picard C, Al‐Herz W, Bousfiha A, et al. (2015) Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015. Journal of Clinical Immunology 35 (8): 696–726.

Pieper K, Rizzi M, Speletas M, et al. (2014) A common single nucleotide polymorphism impairs B‐cell activating factor receptor's multimerization, contributing to common variable immunodeficiency. The Journal of Allergy and Clinical Immunology 133 (4): 1222–1225.

Richards S, Aziz N, Bale S, et al. (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genetics in Medicine 17 (5): 405–424.

Rodriguez‐Cortez VC, Del Pino‐Molina L, Rodriguez‐Ubreva J, et al. (2015) Monozygotic twins discordant for common variable immunodeficiency reveal impaired DNA demethylation during naive‐to‐memory B‐cell transition. Nature Communications 6: 7335.

Salzer U, Chapel HM, Webster AD, et al. (2005) Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nature Genetics 37 (8): 820–828.

Salzer U, Bacchelli C, Buckridge S, et al. (2009) Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease‐causing from risk‐increasing TNFRSF13B variants in antibody deficiency syndromes. Blood 113 (9): 1967–1976.

Salzer E, Santos‐Valente E, Klaver S, et al. (2013) B‐cell deficiency and severe autoimmunity caused by deficiency of protein kinase C delta. Blood 121 (16): 3112–3116.

Salzer E, Kansu A, Sic H, et al. (2014) Early‐onset inflammatory bowel disease and common variable immunodeficiency‐like disease caused by IL‐21 deficiency. The Journal of Allergy and Clinical Immunology 133 (6): 1651–1659.e12.

van Schouwenburg PA, Davenport EE, Kienzler AK, et al. (2015) Application of whole genome and RNA sequencing to investigate the genomic landscape of common variable immunodeficiency disorders. Clinical Immunology 160 (2): 301–314.

Schubert D, Bode C, Kenefeck R, et al. (2014) Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nature Medicine 20 (12): 1410–1416.

Seidel MG, Hirschmugl T, Gamez‐Diaz L, et al. (2015) Long‐term remission after allogeneic hematopoietic stem cell transplantation in LPS‐responsive beige‐like anchor (LRBA) deficiency. The Journal of Allergy and Clinical Immunology 135 (5): 1384–1390.e1‐8.

Stray‐Pedersen A, Sorte HS, Samarakoon P, et al. (2017) Primary immunodeficiency diseases: genomic approaches delineate heterogeneous Mendelian disorders. The Journal of Allergy and Clinical Immunology 139 (1): 232–245.

Szpiech ZA, Xu J, Pemberton TJ, et al. (2013) Long runs of homozygosity are enriched for deleterious variation. American Journal of Human Genetics 93 (1): 90–102.

Thiel J, Kimmig L, Salzer U, et al. (2012) Genetic CD21 deficiency is associated with hypogammaglobulinemia. The Journal of Allergy and Clinical Immunology 129 (3): 801–810.e6.

Tsujita Y, Mitsui‐Sekinaka K, Imai K, et al. (2016) Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3‐kinase delta syndrome‐like immunodeficiency. The Journal of Allergy and Clinical Immunology 138 (6): 1672–1680.e10.

Vignesh P, Rawat A and Singh S (2017) An update on the use of immunomodulators in primary immunodeficiencies. Clinical Reviews in Allergy & Immunology 52 (2): 287–303.

Volk T, Pannicke U, Reisli I, et al. (2015) DCLRE1C (ARTEMIS) mutations causing phenotypes ranging from atypical severe combined immunodeficiency to mere antibody deficiency. Human Molecular Genetics 24 (25): 7361–7372.

Wang HY, Ma CA, Zhao Y, et al. (2013) Antibody deficiency associated with an inherited autosomal dominant mutation in TWEAK. Proceedings of the National Academy of Sciences of the United States of America 110 (13): 5127–5132.

Warnatz K, Salzer U, Rizzi M, et al. (2009) B‐cell activating factor receptor deficiency is associated with an adult‐onset antibody deficiency syndrome in humans. Proceedings of the National Academy of Sciences of the United States of America 106 (33): 13945–13950.

Zhao M, Wang Q, Wang Q, Jia P and Zhao Z (2013) Computational tools for copy number variation (CNV) detection using next‐generation sequencing data: features and perspectives. BMC Bioinformatics 14 (Suppl 11): S1.

van Zelm MC, Reisli I, van der Burg M, et al. (2006) An antibody‐deficiency syndrome due to mutations in the CD19 gene. The New England Journal of Medicine 354 (18): 1901–1912.

van Zelm MC, Smet J, Adams B, et al. (2010) CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency. The Journal of Clinical Investigation 120 (4): 1265–1274.

Further Reading

Bousfiha A, Jeddane L, Al‐Herz W, et al. (2015) The 2015 IUIS phenotypic classification for primary immunodeficiencies. Journal of Clinical Immunology 35 (8): 727–738.

Chapel H (2016) Common variable immunodeficiency disorders (CVID) ‐ Diagnoses of exclusion, especially combined immune defects. The Journal of Allergy and Clinical Immunology. In Practice 4 (6): 1158–1159.

Gathmann B, Mahlaoui N, Gerard L, et al. (2014) Clinical picture and treatment of 2212 patients with common variable immunodeficiency. The Journal of Allergy and Clinical Immunology 134 (1): 116–126.

Kalia SS, Adelman K, Bale SJ, et al. (2017) Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. Genetics in Medicine 19 (2): 249–255.

Kienzler AK, Hargreaves CE and Patel SY (2017) The role of genomics in common variable immunodeficiency disorders. Clinical and Experimental Immunology 188 (3): 326–332.

Li J, Wei Z, Li YR, et al. (2016) Understanding the genetic and epigenetic basis of common variable immunodeficiency disorder through omics approaches. Biochimica et Biophysica Acta 1860 (11 Pt B): 2656–2663.

Maffucci P, Filion CA, Boisson B, et al. (2016) Genetic diagnosis using whole exome sequencing in common variable immunodeficiency. Frontiers in Immunology 7: 220.

Meyts I, Bosch B, Bolze A, et al. (2016) Exome and genome sequencing for inborn errors of immunity. The Journal of Allergy and Clinical Immunology 138 (4): 957–969.

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Bogaert, Delfien J, Dullaers, Melissa, De Baere, Elfride, and Haerynck, Filomeen(Oct 2017) Molecular Genetics of Common Variable Immunodeficiency. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0027265]