Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Beyond monogenetic rare variants: tackling the low rate of genetic diagnoses in predominantly antibody deficiency

Cellular & Molecular Immunology volume 18, pages 588–603 (2021)Cite this article

Subjects

Abstract

Predominantly antibody deficiency (PAD) is the most prevalent form of primary immunodeficiency, and is characterized by broad clinical, immunological and genetic heterogeneity. Utilizing the current gold standard of whole exome sequencing for diagnosis, pathogenic gene variants are only identified in less than 20% of patients. While elucidation of the causal genes underlying PAD has provided many insights into the cellular and molecular mechanisms underpinning disease pathogenesis, many other genes may remain as yet undefined to enable definitive diagnosis, prognostic monitoring and targeted therapy of patients. Considering that many patients display a relatively late onset of disease presentation in their 2nd or 3rd decade of life, it is questionable whether a single genetic lesion underlies disease in all patients. Potentially, combined effects of other gene variants and/or non-genetic factors, including specific infections can drive disease presentation. In this review, we define (1) the clinical and immunological variability of PAD, (2) consider how genetic defects identified in PAD have given insight into B-cell immunobiology, (3) address recent technological advances in genomics and the challenges associated with identifying causal variants, and (4) discuss how functional validation of variants of unknown significance could potentially be translated into increased diagnostic rates, improved prognostic monitoring and personalized medicine for PAD patients. A multidisciplinary approach will be the key to curtailing the early mortality and high morbidity rates in this immune disorder.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  1. Kobrynski, L., Powell, R. W. & Bowen, S. Prevalence and morbidity of primary immunodeficiency diseases, United States 2001–2007. J. Clin. Immunol. 34, 954–961 (2014).

  2. Picard, C. & Fischer, A. Contribution of high-throughput DNA sequencing to the study of primary immunodeficiencies. Eur. J. Immunol. 44, 2854–2861 (2014).

    Article  CAS  PubMed  Google Scholar 

  3. Bucciol, G. et al. Lessons learned from the study of human inborn errors of innate immunity. J. Allergy Clin. Immunol. 143, 507–527 (2019).

    Article  CAS  PubMed  Google Scholar 

  4. Tangye, S. G. et al. Human inborn errors of immunity: 2019 update on the classification from the International Union of Immunological Societies Expert Committee. J. Clin. Immunol. 40, 66–81 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  5. Bousfiha, A. et al. Human inborn errors of immunity: 2019 update of the IUIS phenotypical classification. J. Clin. Immunol. 40, 66–81 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  6. Gathmann, B. et al. The European internet-based patient and research database for primary immunodeficiencies: results 2006-2008. Clin. Exp. Immunol. 157(Suppl 1), 3–11 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Durandy, A., Kracker, S. & Fischer, A. Primary antibody deficiencies. Nat. Rev. Immunol. 13, 519–533 (2013).

    Article  CAS  PubMed  Google Scholar 

  8. Lucas, M. et al. Infection outcomes in patients with common variable immunodeficiency disorders: relationship to immunoglobulin therapy over 22 years. J. Allergy Clin. Immunol. 125, 1354–1360.e1354 (2010).

    Article  CAS  PubMed  Google Scholar 

  9. Bogaert, D. J. et al. Genes associated with common variable immunodeficiency: one diagnosis to rule them all? J. Med. Genet. 53, 575–590 (2016).

    Article  CAS  PubMed  Google Scholar 

  10. Aggarwal, V., Banday, A. Z., Jindal, A. K., Das, J. & Rawat, A. Recent advances in elucidating the genetics of common variable immunodeficiency. Genes Dis. 7, 26–37 (2020).

    Article  CAS  PubMed  Google Scholar 

  11. Bonilla, F. A. et al. International Consensus Document (ICON): common variable immunodeficiency disorders. J. Allergy Clin. Immunol. Pract. 4, 38–59 (2016).

    Article  PubMed  Google Scholar 

  12. Tsukada, S. et al. Deficient expression of a B cell cytoplasmic tyrosine kinase in human X-linked agammaglobulinemia. Cell 72, 279–290 (1993).

    Article  CAS  PubMed  Google Scholar 

  13. Vetrie, D. et al. The gene involved in X-linked agammaglobulinaemia is a member of the src family of protein-tyrosine kinases. Nature 361, 226–233 (1993).

    Article  CAS  PubMed  Google Scholar 

  14. Vorechovsky, I. et al. Molecular diagnosis of X-linked agammaglobulinaemia. Lancet 341, 1153 (1993).

    Article  CAS  PubMed  Google Scholar 

  15. Dingjan, G. M. et al. Bruton’s tyrosine kinase regulates the activation of gene rearrangements at the lambda light chain locus in precursor B cells in the mouse. J. Exp. Med. 193, 1169–1178 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Papapietro, O. et al. Topoisomerase 2beta mutation impairs early B cell development. Blood 135, 1497–1501 (2020).

    Article  PubMed  Google Scholar 

  17. Ben-Ali, M. et al. Homozygous transcription factor 3 gene (TCF3) mutation is associated with severe hypogammaglobulinemia and B-cell acute lymphoblastic leukemia. J. Allergy Clin. Immunol. 140, 1191–1194.e1194 (2017).

    Article  CAS  PubMed  Google Scholar 

  18. Qureshi, S., Sheikh, M. D. A. & Qamar, F. N. Autosomal recessive agammaglobulinemia—first case with a novel TCF3 mutation from Pakistan. Clin. Immunol. 198, 100–101 (2019).

    Article  CAS  PubMed  Google Scholar 

  19. Kuehn, H. S. et al. Loss of B Cells in Patients with Heterozygous Mutations in IKAROS. N. Engl. J. Med. 374, 1032–1043 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yel, L. et al. Mutations in the mu heavy-chain gene in patients with agammaglobulinemia. N. Engl. J. Med. 335, 1486–1493 (1996).

    Article  CAS  PubMed  Google Scholar 

  21. Minegishi, Y. et al. Mutations in Igalpha (CD79a) result in a complete block in B-cell development. J. Clin. Investig. 104, 1115–1121 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Minegishi, Y. et al. Mutations in the human lambda5/14.1 gene result in B cell deficiency and agammaglobulinemia. J. Exp. Med. 187, 71–77 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Minegishi, Y. et al. An essential role for BLNK in human B cell development. Science 286, 1954–1957 (1999).

    Article  CAS  PubMed  Google Scholar 

  24. Dobbs, A. K. et al. Cutting edge: a hypomorphic mutation in Igbeta (CD79b) in a patient with immunodeficiency and a leaky defect in B cell development. J. Immunol. 179, 2055–2059 (2007).

    Article  CAS  PubMed  Google Scholar 

  25. Anzilotti, C. et al. An essential role for the Zn(2+) transporter ZIP7 in B cell development. Nat. Immunol. 20, 350–361 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Broderick, L. et al. Mutations in topoisomerase IIbeta result in a B cell immunodeficiency. Nat. Commun. 10, 3644 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Croker, B. A. et al. The Rac2 guanosine triphosphatase regulates B lymphocyte antigen receptor responses and chemotaxis and is required for establishment of B-1a and marginal zone B lymphocytes. J. Immunol. 168, 3376–3386 (2002).

    Article  CAS  PubMed  Google Scholar 

  28. Alkhairy, O. K. et al. RAC2 loss-of-function mutation in 2 siblings with characteristics of common variable immunodeficiency. J. Allergy Clin. Immunol. 135, 1380–1384.e1-5 (2015).

    Article  CAS  PubMed  Google Scholar 

  29. Elkaim, E. et al. Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase delta syndrome 2: a cohort study. J. Allergy Clin. Immunol. 138, 210–218.e219 (2016).

    Article  CAS  PubMed  Google Scholar 

  30. Sogkas, G. et al. Primary immunodeficiency disorder caused by phosphoinositide 3-kinase delta deficiency. J. Allergy Clin. Immunol. 142, 1650–1653 e1652 (2018).

    Article  PubMed  Google Scholar 

  31. Cohen, S. B. et al. Human primary immunodeficiency caused by expression of a kinase-dead p110delta mutant. J. Allergy Clin. Immunol. 143, 797–799 e792 (2019).

    Article  CAS  PubMed  Google Scholar 

  32. Ramadani, F. et al. The PI3K isoforms p110alpha and p110delta are essential for pre-B cell receptor signaling and B cell development. Sci. Signal. 3, ra60 (2010).

  33. Conley, M. E. et al. Agammaglobulinemia and absent B lineage cells in a patient lacking the p85alpha subunit of PI3K. J. Exp. Med 209, 463–470 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Tang, P. et al. Autosomal recessive agammaglobulinemia due to a homozygous mutation in PIK3R1. J. Clin. Immunol. 38, 88–95 (2018).

    Article  CAS  PubMed  Google Scholar 

  35. Ferrari, S. et al. Mutations of the Igbeta gene cause agammaglobulinemia in man. J. Exp. Med. 204, 2047–2051 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. van Zelm, M. C. et al. Gross deletions involving IGHM, BTK, or Artemis: a model for genomic lesions mediated by transposable elements. Am. J. Hum. Genet. 82, 320–332 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Ameratunga, R. et al. Comparison of diagnostic criteria for common variable immunodeficiency disorder. Front. Immunol. 5, 415 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Boileau, J. et al. Autoimmunity in common variable immunodeficiency: correlation with lymphocyte phenotype in the French DEFI study. J. Autoimmun. 36, 25–32 (2011).

    Article  CAS  PubMed  Google Scholar 

  39. Immunodeficiencies, E. S. F. New Clinical Diagnosis Criteria for the ESID Registry. Geneva. https://esid.org/Working-Parties/Registry/Diagnosis-criteria (2017).

  40. Conley, M. E., Notarangelo, L. D. & Etzioni, A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin. Immunol. 93, 190–197 (1999).

    Article  CAS  PubMed  Google Scholar 

  41. von Spee-Mayer, C. et al. Evaluating laboratory criteria for combined immunodeficiency in adult patients diagnosed with common variable immunodeficiency. Clin. Immunol. 203, 59–62 (2019).

    Article  CAS  Google Scholar 

  42. Bertinchamp, R. et al. Exclusion of patients with a severe T-cell defect improves the definition of common variable immunodeficiency. J. Allergy Clin. Immunol. Pract. 4, 1147–1157 (2016).

    Article  PubMed  Google Scholar 

  43. Chapel, H. Common variable immunodeficiency disorders (CVID)—diagnoses of exclusion, especially combined immune defects. J. Allergy Clin. Immunol. Pr. 4, 1158–1159 (2016).

    Article  Google Scholar 

  44. Grosserichter-Wagener, C. et al. Defective formation of IgA memory B cells, Th1 and Th17 cells in symptomatic patients with selective IgA deficiency. Clin. Transl. Immunol. 9, e1130 (2020).

    Article  CAS  Google Scholar 

  45. Driessen, G. J. et al. Common variable immunodeficiency and idiopathic primary hypogammaglobulinemia: two different conditions within the same disease spectrum. Haematologica 98, 1617–1623 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Cheng, Y. K., Decker, P. A., O’Byrne, M. M. & Weiler, C. R. Specific polysaccharide antibody deficiency syndrome (SPAD): Clinical and laboratory characteristics of seventy seven patients. J. Allergy Clin. Immunol. 115, S158 (2005).

    Article  Google Scholar 

  47. Kim, J. H. et al. Immunoglobulin G subclass deficiency is the major phenotype of primary immunodeficiency in a Korean adult cohort. J. Korean Med. Sci. 25, 824–828 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Resnick, E. S., Moshier, E. L., Godbold, J. H. & Cunningham-Rundles, C. Morbidity and mortality in common variable immune deficiency over 4 decades. Blood 119, 1650–1657 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Jolles, S. Subclinical infection and dosing in primary immunodeficiencies. Clin. Exp. Immunol. 178(Suppl 1), 67–69 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  50. Edwards, E. S. J. et al. Predominantly antibody-deficient patients with non-infectious complications have reduced naive B, Treg, Th17, and Tfh17 cells. Front. Immunol. 10, 2593 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Slade, C. A. et al. Delayed diagnosis and complications of predominantly antibody deficiencies in a cohort of australian adults. Front. Immunol. 9, 694 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Chapel, H. et al. Common variable immunodeficiency disorders: division into distinct clinical phenotypes. Blood 112, 277–286 (2008).

    Article  CAS  PubMed  Google Scholar 

  53. Odnoletkova, I. et al. The burden of common variable immunodeficiency disorders: a retrospective analysis of the European Society for Immunodeficiency (ESID) registry data. Orphanet J. Rare Dis. 13, 201 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  54. Romberg, N. et al. Patients with common variable immunodeficiency with autoimmune cytopenias exhibit hyperplastic yet inefficient germinal center responses. J. Allergy Clin. Immunol. 143, 258–265 (2019).

    Article  PubMed  Google Scholar 

  55. Warnatz, K. et al. Severe deficiency of switched memory B cells (CD27(+)IgM(-)IgD(-)) in subgroups of patients with common variable immunodeficiency: a new approach to classify a heterogeneous disease. Blood 99, 1544–1551 (2002).

    Article  CAS  PubMed  Google Scholar 

  56. Wehr, C. et al. The EUROclass trial: defining subgroups in common variable immunodeficiency. Blood 111, 77–85 (2008).

    Article  CAS  PubMed  Google Scholar 

  57. Blanco, E. et al. Defects in memory B-cell and plasma cell subsets expressing different immunoglobulin-subclasses in patients with CVID and immunoglobulin subclass deficiencies. J. Allergy Clin. Immunol. 144, 809–824 (2019).

    Article  CAS  PubMed  Google Scholar 

  58. Driessen, G. J. et al. B-cell replication history and somatic hypermutation status identify distinct pathophysiologic backgrounds in common variable immunodeficiency. Blood 118, 6814–6823 (2011).

    Article  CAS  PubMed  Google Scholar 

  59. Warnatz, K. & Schlesier, M. Flowcytometric phenotyping of common variable immunodeficiency. Cytom. B Clin. Cytom. 74, 261–271 (2008).

    Article  Google Scholar 

  60. Ebbo, M. et al. Low circulating natural killer cell counts are associated with severe disease in patients with common variable immunodeficiency. EBio Med. 6, 222–230 (2016).

    Google Scholar 

  61. Aspalter, R. M., Sewell, W. A., Dolman, K., Farrant, J. & Webster, A. D. Deficiency in circulating natural killer (NK) cell subsets in common variable immunodeficiency and X-linked agammaglobulinaemia. Clin. Exp. Immunol. 121, 506–514 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Giovannetti, A. et al. Unravelling the complexity of T cell abnormalities in common variable immunodeficiency. J. Immunol. 178, 3932–3943 (2007).

    Article  CAS  PubMed  Google Scholar 

  63. Bateman, E. A. et al. T cell phenotypes in patients with common variable immunodeficiency disorders: associations with clinical phenotypes in comparison with other groups with recurrent infections. Clin. Exp. Immunol. 170, 202–211 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Coraglia, A. et al. Common variable immunodeficiency and circulating TFH. J. Immunol. Res. 2016, 4951587 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  65. Unger, S. et al. The TH1 phenotype of follicular helper T cells indicates an IFN-gamma-associated immune dysregulation in patients with CD21low common variable immunodeficiency. J. Allergy Clin. Immunol. 141, 730–740 (2018).

    Article  CAS  PubMed  Google Scholar 

  66. Romberg, N. D., Hsu, I., Price, C. C., Cunningham-Rundles, C. & Meffre, E. Expansion of circulating T follicular helper cells in CVID patients with autoimmune cytopenias. J. Allergy Clin. Immunol. 133, AB162 (2014).

    Article  Google Scholar 

  67. Barbosa, R. R. et al. Primary B-cell deficiencies reveal a link between human IL-17-producing CD4 T-cell homeostasis and B-cell differentiation. PLoS ONE 6, e22848 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Melo, K. M. et al. A decreased frequency of regulatory T cells in patients with common variable immunodeficiency. PLoS ONE 4, e6269 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Arumugakani, G., Wood, P. M. & Carter, C. R. Frequency of Treg cells is reduced in CVID patients with autoimmunity and splenomegaly and is associated with expanded CD21lo B lymphocytes. J. Clin. Immunol. 30, 292–300 (2010).

    Article  CAS  PubMed  Google Scholar 

  70. Malphettes, M. et al. Late-onset combined immune deficiency: a subset of common variable immunodeficiency with severe T cell defect. Clin. Infect. Dis. 49, 1329–1338 (2009).

    Article  CAS  PubMed  Google Scholar 

  71. Hultberg, J., Ernerudh, J., Larsson, M., Nilsdotter-Augustinsson, A. & Nystrom, S. Plasma protein profiling reflects TH1-driven immune dysregulation in common variable immunodeficiency. J. Allergy Clin. Immunol. 146, 417–428 (2020).

    Article  CAS  PubMed  Google Scholar 

  72. Cols, M. et al. Expansion of inflammatory innate lymphoid cells in patients with common variable immune deficiency. J. Allergy Clin. Immunol. 137, 1206–1215 e1206 (2016).

    Article  CAS  PubMed  Google Scholar 

  73. Berkowska, M. A., van der Burg, M., van Dongen, J. J. & van Zelm, M. C. Checkpoints of B cell differentiation: visualizing Ig-centric processes. Ann. N.Y. Acad. Sci. 1246, 11–25 (2011).

    Article  CAS  PubMed  Google Scholar 

  74. Clark, M. R., Mandal, M., Ochiai, K. & Singh, H. Orchestrating B cell lymphopoiesis through interplay of IL-7 receptor and pre-B cell receptor signalling. Nat. Rev. Immunol. 14, 69–80 (2014).

    Article  CAS  PubMed  Google Scholar 

  75. Boisson, B. et al. A recurrent dominant negative E47 mutation causes agammaglobulinemia and BCR(-) B cells. J. Clin. Investig. 123, 4781–4785 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Rohrer, J., Minegishi, Y., Richter, D., Eguiguren, J. & Conley, M. E. Unusual mutations in Btk: an insertion, a duplication, an inversion, and four large deletions. Clin. Immunol. 90, 28–37 (1999).

    Article  CAS  PubMed  Google Scholar 

  77. Vihinen, M. et al. Mutations of the human BTK gene coding for bruton tyrosine kinase in X-linked agammaglobulinemia. Hum. Mutat. 13, 280–285 (1999).

    Article  CAS  PubMed  Google Scholar 

  78. Kumaki, E. et al. Atypical SIFD with novel TRNT1 mutations: a case study on the pathogenesis of B-cell deficiency. Int. J. Hematol. 109, 382–389 (2019).

    Article  CAS  PubMed  Google Scholar 

  79. Wedatilake, Y. et al. TRNT1 deficiency: clinical, biochemical and molecular genetic features. Orphanet J. Rare Dis. 11, 90 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  80. Meyers, G. et al. Activation-induced cytidine deaminase (AID) is required for B-cell tolerance in humans. Proc. Natl Acad. Sci. USA 108, 11554–11559 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Warnatz, K. et al. B-cell activating factor receptor deficiency is associated with an adult-onset antibody deficiency syndrome in humans. Proc. Natl Acad. Sci. USA 106, 13945–13950 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Losi, C. G. et al. Mutational analysis of human BAFF receptor TNFRSF13C (BAFF-R) in patients with common variable immunodeficiency. J. Clin. Immunol. 25, 496–502 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Wang, H. Y. et al. Antibody deficiency associated with an inherited autosomal dominant mutation in TWEAK. Proc. Natl Acad. Sci. USA 110, 5127–5132 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Cherukuri, A., Cheng, P. C., Sohn, H. W. & Pierce, S. K. The CD19/CD21 complex functions to prolong B cell antigen receptor signaling from lipid rafts. Immunity 14, 169–179 (2001).

    Article  CAS  PubMed  Google Scholar 

  85. Carter, R. H. & Fearon, D. T. CD19: lowering the threshold for antigen receptor stimulation of B lymphocytes. Science 256, 105–107 (1992).

    Article  CAS  PubMed  Google Scholar 

  86. van Noesel, C. J., Lankester, A. C. & van Lier, R. A. Dual antigen recognition by B cells. Immunol. Today 14, 8–11 (1993).

    Article  PubMed  Google Scholar 

  87. van Zelm, M. C. et al. Human CD19 and CD40L deficiencies impair antibody selection and differentially affect somatic hypermutation. J. Allergy Clin. Immunol. 134, 135–144 (2014).

    Article  PubMed  CAS  Google Scholar 

  88. van Zelm, M. C. et al. CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency. J. Clin. Investig. 120, 1265–1274 (2010).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  89. van Zelm, M. C. et al. Antibody deficiency due to a missense mutation in CD19 demonstrates the importance of the conserved tryptophan 41 in immunoglobulin superfamily domain formation. Hum. Mol. Genet. 20, 1854–1863 (2011).

    Article  PubMed  CAS  Google Scholar 

  90. Wentink, M. W. et al. CD21 and CD19 deficiency: two defects in the same complex leading to different disease modalities. Clin. Immunol. 161, 120–127 (2015).

    Article  CAS  PubMed  Google Scholar 

  91. Thiel, J. et al. Genetic CD21 deficiency is associated with hypogammaglobulinemia. J. Allergy Clin. Immunol. 129, 801–810 e806 (2012).

    Article  CAS  PubMed  Google Scholar 

  92. Jansen, E. J. et al. ATP6AP1 deficiency causes an immunodeficiency with hepatopathy, cognitive impairment and abnormal protein glycosylation. Nat. Commun. 7, 11600 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Oellerich, T. et al. The B-cell antigen receptor signals through a preformed transducer module of SLP65 and CIN85. EMBO J. 30, 3620–3634 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Keller, B. et al. Germline deletion of CIN85 in humans with X chromosome-linked antibody deficiency. J. Exp. Med. 215, 1327–1336 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. van Zelm, M. C. et al. An antibody-deficiency syndrome due to mutations in the CD19 gene. N. Engl. J. Med. 354, 1901–1912 (2006).

    Article  PubMed  Google Scholar 

  96. Kuijpers, T. W. et al. CD20 deficiency in humans results in impaired T cell-independent antibody responses. J. Clin. Investig. 120, 214–222 (2010).

    Article  CAS  PubMed  Google Scholar 

  97. Snow, A. L. et al. Congenital B cell lymphocytosis explained by novel germline CARD11 mutations. J. Exp. Med. 209, 2247–2261 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Polyak, M. J., Li, H., Shariat, N. & Deans, J. P. CD20 homo-oligomers physically associate with the B cell antigen receptor. Dissociation upon receptor engagement and recruitment of phosphoproteins and calmodulin-binding proteins. J. Biol. Chem. 283, 18545–18552 (2008).

    Article  CAS  PubMed  Google Scholar 

  99. Petrie, R. J. & Deans, J. P. Colocalization of the B cell receptor and CD20 followed by activation-dependent dissociation in distinct lipid rafts. J. Immunol. 169, 2886–2891 (2002).

    Article  CAS  PubMed  Google Scholar 

  100. Kranich, J. & Krautler, N. J. How follicular dendritic cells shape the B-Cell antigenome. Front. Immunol. 7, 225 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. MacLennan, I. C. Germinal centers. Annu. Rev. Immunol. 12, 117–139 (1994).

    Article  CAS  PubMed  Google Scholar 

  102. Bhushan, A. & Covey, L. R. CD40:CD40L interactions in X-linked and non-X-linked hyper-IgM syndromes. Immunol. Res. 24, 311–324 (2001).

    Article  CAS  PubMed  Google Scholar 

  103. Castigli, E. et al. CD40 ligand/CD40 deficiency. Int. Arch. Allergy Immunol. 107, 37–39 (1995).

    Article  CAS  PubMed  Google Scholar 

  104. Chou, J. et al. A novel mutation in ICOS presenting as hypogammaglobulinemia with susceptibility to opportunistic pathogens. J. Allergy Clin. Immunol. 136, 794–797.e791 (2015).

    Article  CAS  PubMed  Google Scholar 

  105. Grimbacher, B. et al. Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat. Immunol. 4, 261–268 (2003).

    Article  CAS  PubMed  Google Scholar 

  106. Salzer, U. et al. ICOS deficiency in patients with common variable immunodeficiency. Clin. Immunol. 113, 234–240 (2004).

    Article  CAS  PubMed  Google Scholar 

  107. Warnatz, K. et al. Human ICOS deficiency abrogates the germinal center reaction and provides a monogenic model for common variable immunodeficiency. Blood 107, 3045–3052 (2006).

    Article  CAS  PubMed  Google Scholar 

  108. Roussel, L. et al. Loss of human ICOSL results in combined immunodeficiency. J. Exp. Med. 215, 3151–3164 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Revy, P. et al. Activation-induced cytidine deaminase (AID) deficiency causes the autosomal recessive form of the Hyper-IgM syndrome (HIGM2). Cell 102, 565–575 (2000).

    Article  CAS  PubMed  Google Scholar 

  110. Imai, K. et al. Human uracil-DNA glycosylase deficiency associated with profoundly impaired immunoglobulin class-switch recombination. Nat. Immunol. 4, 1023–1028 (2003).

    Article  CAS  PubMed  Google Scholar 

  111. Gardes, P. et al. Human MSH6 deficiency is associated with impaired antibody maturation. J. Immunol. 188, 2023–2029 (2012).

    Article  CAS  PubMed  Google Scholar 

  112. Kracker, S. et al. An inherited immunoglobulin class-switch recombination deficiency associated with a defect in the INO80 chromatin remodeling complex. J. Allergy Clin. Immunol. 135, 998–1007 e1006 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Castigli, E. et al. TACI is mutant in common variable immunodeficiency and IgA deficiency. Nat. Genet. 37, 829–834 (2005).

    Article  CAS  PubMed  Google Scholar 

  114. Knight, A. K. et al. High serum levels of BAFF, APRIL, and TACI in common variable immunodeficiency. Clin. Immunol. 124, 182–189 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Pan-Hammarstrom, Q. et al. Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency. Nat. Genet. 39, 429–430 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Romberg, N. et al. CVID-associated TACI mutations affect autoreactive B cell selection and activation. J. Clin. Investig. 123, 4283–4293 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Salzer, U. et al. Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes. Blood 113, 1967–1976 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Salzer, U. et al. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat. Genet. 37, 820–828 (2005).

    Article  CAS  PubMed  Google Scholar 

  119. Zhang, L. et al. Transmembrane activator and calcium-modulating cyclophilin ligand interactor mutations in common variable immunodeficiency: clinical and immunologic outcomes in heterozygotes. J. Allergy Clin. Immunol. 120, 1178–1185 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Almejun, M. B. et al. Naturally occurring mutation affecting the MyD88-binding site of TNFRSF13B impairs triggering of class switch recombination. Eur. J. Immunol. 43, 805–814 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Scott, O. & Roifman, C. M. NF-kappaB pathway and the Goldilocks principle: Lessons from human disorders of immunity and inflammation. J. Allergy Clin. Immunol. 143, 1688–1701 (2019).

    Article  PubMed  Google Scholar 

  122. Tangye, S. G. et al. Immune dysregulation and disease pathogenesis due to activating mutations in PIK3CD-the Goldilocks’ effect. J. Clin. Immunol. 39, 148–158 (2019).

    Article  CAS  PubMed  Google Scholar 

  123. Deau, M. C. et al. A human immunodeficiency caused by mutations in the PIK3R1 gene. J. Clin. Investig. 124, 3923–3928 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Lucas, C. L. et al. Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K. J. Exp. Med. 211, 2537–2547 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Avery, D. T. et al. Germline-activating mutations in PIK3CD compromise B cell development and function. J. Exp. Med. 215, 2073–2095 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Wentink, M. et al. Genetic defects in PI3Kdelta affect B-cell differentiation and maturation leading to hypogammaglobulineamia and recurrent infections. Clin. Immunol. 176, 77–86 (2017).

    Article  CAS  PubMed  Google Scholar 

  127. Bouafia, A. et al. Loss of ARHGEF1 causes a human primary antibody deficiency. J. Clin. Investig. 129, 1047–1060 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  128. Mathew, D., Kremer, K. N. & Torres, R. M. ARHGEF1 deficiency reveals Galpha13-associated GPCRs are critical regulators of human lymphocyte function. J. Clin. Investig. 129, 965–968 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  129. Tsujita, Y. et al. Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase delta syndrome-like immunodeficiency. J. Allergy Clin. Immunol. 138, 1672–1680 e1610 (2016).

    Article  CAS  PubMed  Google Scholar 

  130. Browning, M. J., Chandra, A., Carbonaro, V., Okkenhaug, K. & Barwell, J. Cowden’s syndrome with immunodeficiency. J. Med. Genet. 52, 856–859 (2015).

    Article  CAS  PubMed  Google Scholar 

  131. Dornan, G. L. et al. Conformational disruption of PI3Kdelta regulation by immunodeficiency mutations in PIK3CD and PIK3R1. Proc. Natl Acad. Sci. USA 114, 1982–1987 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Kaustio, M. et al. Damaging heterozygous mutations in NFKB1 lead to diverse immunologic phenotypes. J. Allergy Clin. Immunol. 140, 782–796 (2017).

    Article  CAS  PubMed  Google Scholar 

  133. Lorenzini, T. et al. Characterization of the clinical and immunological phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations. J Allergy Clin. Immunol. (2020). (In press)

  134. Tuijnenburg, P. et al. Loss-of-function nuclear factor kappaB subunit 1 (NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans. J. Allergy Clin. Immunol. 142, 1285–1296 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Kuehn, H. S. et al. Novel nonsense gain-of-function NFKB2 mutations associated with a combined immunodeficiency phenotype. Blood 130, 1553–1564 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Boztug, H. et al. NF-kappaB1 haploinsufficiency causing immunodeficiency and ebv-driven lymphoproliferation. J. Clin. Immunol. 36, 533–540 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Fliegauf, M. et al. Haploinsufficiency of the NF-kappaB1 subunit p50 in common variable immunodeficiency. Am. J. Hum. Genet. 97, 389–403 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Aird, A. et al. Novel heterozygous mutation in NFKB2 is associated with early onset CVID and a functional defect in NK cells complicated by disseminated CMV infection and severe nephrotic syndrome. Front. Pediatr. 7, 303 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  139. Brue, T. et al. Mutations in NFKB2 and potential genetic heterogeneity in patients with DAVID syndrome, having variable endocrine and immune deficiencies. BMC Med. Genet. 15, 139 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Chen, K. et al. Germline mutations in NFKB2 implicate the noncanonical NF-kappaB pathway in the pathogenesis of common variable immunodeficiency. Am. J. Hum. Genet. 93, 812–824 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Klemann, C. et al. Clinical and immunological phenotype of patients with primary immunodeficiency due to damaging mutations in NFKB2. Front. Immunol. 10, 297 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Lee, C. E. et al. Autosomal-dominant B-cell deficiency with alopecia due to a mutation in NFKB2 that results in nonprocessable p100. Blood 124, 2964–2972 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Lindsley, A. W. et al. Combined immune deficiency in a patient with a novel NFKB2 mutation. J. Clin. Immunol. 34, 910–915 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Shi, C. et al. NFKB2 mutation in common variable immunodeficiency and isolated adrenocorticotropic hormone deficiency: a case report and review of literature. Medicine 95, e5081 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Angulo, I. et al. Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage. Science 342, 866–871 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Coulter, T. I. et al. Clinical spectrum and features of activated phosphoinositide 3-kinase delta syndrome: a large patient cohort study. J. Allergy Clin. Immunol. 139, 597–606.e594 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  147. Lucas, C. L., Chandra, A., Nejentsev, S., Condliffe, A. M. & Okkenhaug, K. PI3Kdelta and primary immunodeficiencies. Nat. Rev. Immunol. 16, 702–714 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Lucas, C. L. et al. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110delta result in T cell senescence and human immunodeficiency. Nat. Immunol. 15, 88–97 (2014).

    Article  CAS  PubMed  Google Scholar 

  149. Preite, S., Gomez-Rodriguez, J., Cannons, J. L. & Schwartzberg, P. L. T and B-cell signaling in activated PI3K delta syndrome: from immunodeficiency to autoimmunity. Immunol. Rev. 291, 154–173 (2019).

    Article  CAS  PubMed  Google Scholar 

  150. Bier, J. et al. Activating mutations in PIK3CD disrupt the differentiation and function of human and murine CD4(+) T cells. J. Allergy Clin. Immunol. 144, 236–253 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Edwards, E. S. J. et al. Activating PIK3CD mutations impair human cytotoxic lymphocyte differentiation and function and EBV immunity. J. Allergy Clin. Immunol. 143, 276–291.e276 (2019).

    Article  CAS  PubMed  Google Scholar 

  152. Ruiz-Garcia, R. et al. Mutations in PI3K110delta cause impaired natural killer cell function partially rescued by rapamycin treatment. J. Allergy Clin. Immunol. 142, 605–617.e607 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Perez-Andres, M. et al. Human peripheral blood B-cell compartments: a crossroad in B-cell traffic. Cytom. B Clin. Cytom. 78(Suppl 1), S47–S60 (2010).

    Article  CAS  Google Scholar 

  154. Bolar, N. A. et al. Heterozygous loss-of-function SEC61A1 mutations cause autosomal-dominant tubulo-interstitial and glomerulocystic kidney disease with anemia. Am. J. Hum. Genet. 99, 174–187 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Schubert, D. et al. Plasma cell deficiency in human subjects with heterozygous mutations in Sec61 translocon alpha 1 subunit (SEC61A1). J. Allergy Clin. Immunol. 141, 1427–1438 (2018).

    Article  CAS  PubMed  Google Scholar 

  156. Keller, M. D. et al. Mutation in IRF2BP2 is responsible for a familial form of common variable immunodeficiency disorder. J. Allergy Clin. Immunol. 138, 544–550 e544 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  157. Yeh, T. W. O., et al. APRIL-dependent life-long plasmacyte maintenance and immunoglobulin production in humans. J. Allergy Clin. Immunol. S0091-6749(20)30432-2 (2020). [Epub ahead of print].

  158. Sadat, M. A. et al. Glycosylation, hypogammaglobulinemia, and resistance to viral infections. N. Engl. J. Med. 370, 1615–1625 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Bruton, O. C. Agammaglobulinemia. Pediatrics 9, 722–728 (1952).

    Article  CAS  PubMed  Google Scholar 

  160. Chinn, I. K. et al. Diagnostic interpretation of genetic studies in patients with primary immunodeficiency diseases: a working group report of the Primary Immunodeficiency Diseases Committee of the American Academy of Allergy, Asthma & Immunology. J. Allergy Clin. Immunol. 145, 46–69 (2020).

    Article  CAS  PubMed  Google Scholar 

  161. Meyts, I. et al. Exome and genome sequencing for inborn errors of immunity. J. Allergy Clin. Immunol. 138, 957–969 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Itan, Y. & Casanova, J. L. Novel primary immunodeficiency candidate genes predicted by the human gene connectome. Front. Immunol. 6, 142 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  163. Mu, W., Lu, H. M., Chen, J., Li, S. & Elliott, A. M. Sanger confirmation is required to achieve optimal sensitivity and specificity in next-generation sequencing panel testing. J. Mol. Diagn. 18, 923–932 (2016).

    Article  CAS  PubMed  Google Scholar 

  164. Collins, F. S., Morgan, M. & Patrinos, A. The Human Genome Project: lessons from large-scale biology. Science 300, 286–290 (2003).

    Article  CAS  PubMed  Google Scholar 

  165. International Human Genome Sequencing, C. Finishing the euchromatic sequence of the human genome. Nature 431, 931–945 (2004).

    Article  CAS  Google Scholar 

  166. Fang, M., Abolhassani, H., Lim, C. K., Zhang, J. & Hammarstrom, L. Next generation sequencing data analysis in primary immunodeficiency disorders—future directions. J. Clin. Immunol. 36(Suppl 1), 68–75 (2016).

    Article  CAS  PubMed  Google Scholar 

  167. Conley, M. E. & Casanova, J. L. Discovery of single-gene inborn errors of immunity by next generation sequencing. Curr. Opin. Immunol. 30, 17–23 (2014).

    Article  CAS  PubMed  Google Scholar 

  168. Oliveira, J. B. & Fleisher, T. A. Laboratory evaluation of primary immunodeficiencies. J. Allergy Clin. Immunol. 125, S297–S305 (2010).

    Article  PubMed  Google Scholar 

  169. Moens, L. N. et al. Diagnostics of primary immunodeficiency diseases: a sequencing capture approach. PLoS ONE 9, e114901 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  170. Nijman, I. J. et al. Targeted next-generation sequencing: a novel diagnostic tool for primary immunodeficiencies. J. Allergy Clin. Immunol. 133, 529–534 (2014).

    Article  CAS  PubMed  Google Scholar 

  171. Stoddard, J. L., Niemela, J. E., Fleisher, T. A. & Rosenzweig, S. D. Targeted NGS: a cost-effective approach to molecular diagnosis of PIDs. Front. Immunol. 5, 531 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  172. Chou, J., Ohsumi, T. K. & Geha, R. S. Use of whole exome and genome sequencing in the identification of genetic causes of primary immunodeficiencies. Curr. Opin. Allergy Clin. Immunol. 12, 623–628 (2012).

    Article  CAS  PubMed  Google Scholar 

  173. Bamshad, M. J. et al. Exome sequencing as a tool for Mendelian disease gene discovery. Nat. Rev. Genet. 12, 745–755 (2011).

    Article  CAS  PubMed  Google Scholar 

  174. Hodges, E. et al. Genome-wide in situ exon capture for selective resequencing. Nat. Genet. 39, 1522–1527 (2007).

    Article  CAS  PubMed  Google Scholar 

  175. Dyer, L. et al. Gene dosage defects in primary immunodeficiencies and related disorders: a pilot study. J. Transl. Genet. Genom. 1, 23–27 (2017).

    Article  Google Scholar 

  176. Thaventhiran, J. E. D. et al. Whole-genome sequencing of a sporadic primary immunodeficiency cohort. Nature 583, 90–95 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Belkadi, A. et al. Whole-genome sequencing is more powerful than whole-exome sequencing for detecting exome variants. Proc. Natl Acad. Sci. USA 112, 5473–5478 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  178. Lek, M. et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature 536, 285–291 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Richards, S. et al. 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. Genet. Med. 17, 405–424 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  180. Stenson, P. D. et al. The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum. Genet. 133, 1–9 (2014).

    Article  CAS  PubMed  Google Scholar 

  181. Jalali Sefid Dashti, M. & Gamieldien, J. A practical guide to filtering and prioritizing genetic variants. Biotechniques 62, 18–30 (2017).

    Article  PubMed  CAS  Google Scholar 

  182. Kobayashi, Y. et al. Pathogenic variant burden in the ExAC database: an empirical approach to evaluating population data for clinical variant interpretation. Genome Med. 9, 13 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  183. Casanova, J. L., Conley, M. E., Seligman, S. J., Abel, L. & Notarangelo, L. D. Guidelines for genetic studies in single patients: lessons from primary immunodeficiencies. J. Exp. Med. 211, 2137–2149 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Kumar, P., Henikoff, S. & Ng, P. C. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat. Protoc. 4, 1073–1081 (2009).

    Article  CAS  PubMed  Google Scholar 

  185. Adzhubei, I. A. et al. A method and server for predicting damaging missense mutations. Nat. Methods 7, 248–249 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Fischer, A. & Rausell, A. What do primary immunodeficiencies tell us about the essentiality/redundancy of immune responses? Semin. Immunol. 36, 13–16 (2018).

    Article  CAS  PubMed  Google Scholar 

  187. Zhang, S. Y. et al. Human inborn errors of immunity to infection affecting cells other than leukocytes: from the immune system to the whole organism. Curr. Opin. Immunol. 59, 88–100 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Ma, C. A. et al. Germline hypomorphic CARD11 mutations in severe atopic disease. Nat. Genet. 49, 1192–1201 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Felgentreff, K. et al. Functional analysis of naturally occurring DCLRE1C mutations and correlation with the clinical phenotype of ARTEMIS deficiency. J. Allergy Clin. Immunol. 136, 140–150.e147 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Gutierrez-Rodrigues, F. & Calado, R. T. The interpretation of rare or novel variants: damaging vs. disease-causing. Rev. Bras. Hematol. Hemoter. 40, 3–4 (2018).

    PubMed  Google Scholar 

  191. Gallo, V. et al. Diagnostics of primary immunodeficiencies through next-generation sequencing. Front. Immunol. 7, 466 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  192. van Schouwenburg, P. A. et al. Application of whole genome and RNA sequencing to investigate the genomic landscape of common variable immunodeficiency disorders. Clin. Immunol. 160, 301–314 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  193. de Valles-Ibanez, G. et al. Evaluating the genetics of common variable immunodeficiency: monogenetic model and beyond. Front. Immunol. 9, 636 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  194. Christiansen, M. et al. Identification of novel genetic variants in CVID patients with autoimmunity, autoinflammation, or malignancy. Front. Immunol. 10, 3022 (2019).

    Article  CAS  PubMed  Google Scholar 

  195. Stuchly, J. et al. Common Variable Immunodeficiency patients with a phenotypic profile of immunosenescence present with thrombocytopenia. Sci. Rep. 7, 39710 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Maffucci, P. et al. Genetic diagnosis using whole exome sequencing in common variable immunodeficiency. Front. Immunol. 7, 220 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  197. Abolhassani, H. et al. Clinical implications of systematic phenotyping and exome sequencing in patients with primary antibody deficiency. Genet. Med. 21, 243–251 (2019).

    Article  CAS  PubMed  Google Scholar 

  198. Schwab, C. et al. Phenotype, penetrance, and treatment of 133 cytotoxic T-lymphocyte antigen 4-insufficient subjects. J. Allergy Clin. Immunol. 142, 1932–1946 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Mahmoud, M. et al. Structural variant calling: the long and the short of it. Genome Biol. 20, 246 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  200. Keller, M. et al. Burden of copy number variation in common variable immunodeficiency. Clin. Exp. Immunol. 177, 269–271 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Stray-Pedersen, A. et al. Primary immunodeficiency diseases: genomic approaches delineate heterogeneous Mendelian disorders. J. Allergy Clin. Immunol. 139, 232–245 (2017).

    Article  PubMed  Google Scholar 

  202. Orange, J. S. et al. Genome-wide association identifies diverse causes of common variable immunodeficiency. J. Allergy Clin. Immunol. 127, 1360–1367.e1366 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. de Bakker, P. I. et al. A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nat. Genet. 38, 1166–1172 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  204. Li, J. et al. Association of CLEC16A with human common variable immunodeficiency disorder and role in murine B cells. Nat. Commun. 6, 6804 (2015).

    Article  CAS  PubMed  Google Scholar 

  205. Kumar, V., Wijmenga, C. & Xavier, R. J. Genetics of immune-mediated disorders: from genome-wide association to molecular mechanism. Curr. Opin. Immunol. 31, 51–57 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. David, T., Ling, S. F. & Barton, A. Genetics of immune-mediated inflammatory diseases. Clin. Exp. Immunol. 193, 3–12 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Olerup, O., Smith, C. I., Bjorkander, J. & Hammarstrom, L. Shared HLA class II-associated genetic susceptibility and resistance, related to the HLA-DQB1 gene, in IgA deficiency and common variable immunodeficiency. Proc. Natl Acad. Sci. USA 89, 10653–10657 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Maggadottir, S. M. et al. Rare variants at 16p11.2 are associated with common variable immunodeficiency. J. Allergy Clin. Immunol. 135, 1569–1577 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Fiorillo, E. et al. Autoimmune-associated PTPN22 R620W variation reduces phosphorylation of lymphoid phosphatase on an inhibitory tyrosine residue. J. Biol. Chem. 285, 26506–26518 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Chew, G. Y. et al. Autoimmunity in primary antibody deficiency is associated with protein tyrosine phosphatase nonreceptor type 22 (PTPN22). J. Allergy Clin. Immunol. 131, 1130–1135.1135.e1131 (2013).

    Article  CAS  PubMed  Google Scholar 

  211. Kalina, T. et al. CD maps-dynamic profiling of CD1-CD100 surface expression on human leukocyte and lymphocyte subsets. Front. Immunol. 10, 2434 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. van Zelm, M. C. et al. Functional antibody responses following allogeneic stem cell transplantation for TP53 mutant pre-B-ALL in a patient with X-linked agammaglobulinemia. Front. Immunol. 10, 895 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  213. Gaspar, H. B., Lester, T., Levinsky, R. J. & Kinnon, C. Bruton’s tyrosine kinase expression and activity in X-linked agammaglobulinaemia (XLA): the use of protein analysis as a diagnostic indicator of XLA. Clin. Exp. Immunol. 111, 334–338 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Abolhassani, H. et al. Combined immunodeficiency and Epstein-Barr virus-induced B cell malignancy in humans with inherited CD70 deficiency. J. Exp. Med. 214, 91–106 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Caorsi, R. et al. CD70 deficiency due to a novel mutation in a patient with severe chronic EBV infection presenting as a periodic fever. Front. Immunol. 8, 2015 (2017).

    Article  PubMed  CAS  Google Scholar 

  216. Izawa, K. et al. Inherited CD70 deficiency in humans reveals a critical role for the CD70-CD27 pathway in immunity to Epstein-Barr virus infection. J. Exp. Med. 214, 73–89 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Lopez-Herrera, G. et al. Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity. Am. J. Hum. Genet. 90, 986–1001 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Okeke, E. B. et al. Deficiency of phosphatidylinositol 3-kinase delta signaling leads to diminished numbers of regulatory T cells and increased neutrophil activity resulting in mortality due to endotoxic shock. J. Immunol. 199, 1086–1095 (2017).

    Article  CAS  PubMed  Google Scholar 

  219. Edwards, E. S. J., et al. Predominantly antibody-deficient patients with non-infectious complications have reduced naive B, Treg, Th17 and Tfh17 cells. Front. Immunol. (2019).

  220. Wherry, E. J. et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27, 670–684 (2007).

    Article  CAS  PubMed  Google Scholar 

  221. Xu, W. & Larbi, A. Markers of T cell senescence in humans. Int. J. Mol. Sci. 18, 1742 (2017).

    Article  PubMed Central  CAS  Google Scholar 

  222. Bercovici, N., Duffour, M. T., Agrawal, S., Salcedo, M. & Abastado, J. P. New methods for assessing T-cell responses. Clin. Diagn. Lab. Immunol. 7, 859–864 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  223. Ghosh, S. et al. Extended clinical and immunological phenotype and transplant outcome in CD27 and CD70 deficiency. Blood (2020). [Epub ahead of print].

  224. Whittle, J. R. et al. Flow cytometry reveals that H5N1 vaccination elicits cross-reactive stem-directed antibodies from multiple Ig heavy-chain lineages. J. Virol. 88, 4047–4057 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  225. Wheatley, A. K., Kristensen, A. B., Lay, W. N. & Kent, S. J. HIV-dependent depletion of influenza-specific memory B cells impacts B cell responsiveness to seasonal influenza immunisation. Sci. Rep. 6, 26478 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Hartley, G. E., et al. Influenza-specific IgG1+ memory B cell numbers increase upon booster vaccination in healthy adults but not in patients with Predominantly Antibody Deficiency. Under review (2020).

  227. Fischer, M. B. et al. A defect in the early phase of T-cell receptor-mediated T-cell activation in patients with common variable immunodeficiency. Blood 84, 4234–4241 (1994).

    Article  CAS  PubMed  Google Scholar 

  228. Li, F. Y. et al. Second messenger role for Mg2+ revealed by human T-cell immunodeficiency. Nature 475, 471–476 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Chaigne-Delalande, B. et al. Mg2+ regulates cytotoxic functions of NK and CD8 T cells in chronic EBV infection through NKG2D. Science 341, 186–191 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Tario, J. D. Jr., Conway, A. N., Muirhead, K. A. & Wallace, P. K. Monitoring cell proliferation by dye dilution: considerations for probe selection. Methods Mol. Biol. 1678, 249–299 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  231. French, M. A. & Harrison, G. Serum IgG subclass concentrations in healthy adults: a study using monoclonal antisera. Clin. Exp. Immunol. 56, 473–475 (1984).

    CAS  PubMed  PubMed Central  Google Scholar 

  232. Berneman, A., Belec, L., Fischetti, V. A. & Bouvet, J. P. The specificity patterns of human immunoglobulin G antibodies in serum differ from those in autologous secretions. Infect. Immun. 66, 4163–4168 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Klinken, E. M. et al. Diversity of XMEN disease: description of 2 novel variants and analysis of the lymphocyte phenotype. J. Clin. Immunol. 40, 299–309 (2020).

    Article  CAS  PubMed  Google Scholar 

  234. Sallusto, F. & Lanzavecchia, A. Heterogeneity of CD4+ memory T cells: functional modules for tailored immunity. Eur. J. Immunol. 39, 2076–2082 (2009).

    Article  CAS  PubMed  Google Scholar 

  235. Coulter, T. I. & Cant, A. J. The treatment of activated PI3Kdelta syndrome. Front Immunol. 9, 2043 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  236. Maccari, M. E. et al. Disease evolution and response to rapamycin in activated phosphoinositide 3-kinase delta syndrome: the European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase delta Syndrome Registry. Front. Immunol. 9, 543 (2018).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  237. Rao, V. K. et al. Effective “activated PI3Kdelta syndrome”-targeted therapy with the PI3Kdelta inhibitor leniolisib. Blood 130, 2307–2316 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Cahn, A. et al. Safety, pharmacokinetics and dose-response characteristics of GSK2269557, an inhaled PI3Kdelta inhibitor under development for the treatment of COPD. Pulm. Pharm. Ther. 46, 69–77 (2017).

    Article  CAS  Google Scholar 

  239. Kuehn, H. S. et al. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4. Science 345, 1623–1627 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Lo, B. et al. Autoimmune disease. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science 349, 436–440 (2015).

    Article  CAS  PubMed  Google Scholar 

  241. Schubert, D. et al. Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations. Nat. Med. 20, 1410–1416 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Alangari, A. et al. LPS-responsive beige-like anchor (LRBA) gene mutation in a family with inflammatory bowel disease and combined immunodeficiency. J. Allergy Clin. Immunol. 130, 481–488 e482 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Burns, S. O. et al. LRBA gene deletion in a patient presenting with autoimmunity without hypogammaglobulinemia. J. Allergy Clin. Immunol. 130, 1428–1432 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Revel-Vilk, S. et al. Autoimmune lymphoproliferative syndrome-like disease in patients with LRBA mutation. Clin. Immunol. 159, 84–92 (2015).

    Article  CAS  PubMed  Google Scholar 

  245. Lee, S. et al. Abatacept alleviates severe autoimmune symptoms in a patient carrying a de novo variant in CTLA-4. J. Allergy Clin. Immunol. 137, 327–330 (2016).

    Article  PubMed  Google Scholar 

  246. van Leeuwen, E. M., Cuadrado, E., Gerrits, A. M., Witteveen, E. & de Bree, G. J. Treatment of Intracerebral Lesions with Abatacept in a CTLA4-Haploinsufficient Patient. J. Clin. Immunol. 38, 464–467 (2018).

    Article  PubMed  CAS  Google Scholar 

  247. Liu, L. et al. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J. Exp. Med. 208, 1635–1648 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. van de Veerdonk, F. L. et al. STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N. Engl. J. Med. 365, 54–61 (2011).

    Article  PubMed  Google Scholar 

  249. Boisson-Dupuis, S. et al. Inborn errors of human STAT1: allelic heterogeneity governs the diversity of immunological and infectious phenotypes. Curr. Opin. Immunol. 24, 364–378 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Toubiana, J. et al. Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype. Blood 127, 3154–3164 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. van Zelm, M. C. et al. Impaired STAT3-dependent upregulation of IL2Ralpha in B cells of a patient with a STAT1 gain-of-function mutation. Front. Immunol. 10, 768 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  252. Kobbe, R. et al. 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, 234–238 (2016).

    Article  CAS  PubMed  Google Scholar 

  253. Ramana, C. V., Chatterjee-Kishore, M., Nguyen, H. & Stark, G. R. Complex roles of Stat1 in regulating gene expression. Oncogene 19, 2619–2627 (2000).

    Article  CAS  PubMed  Google Scholar 

  254. Forbes, L. R. et al. Jakinibs for the treatment of immune dysregulation in patients with gain-of-function signal transducer and activator of transcription 1 (STAT1) or STAT3 mutations. J. Allergy Clin. Immunol. 142, 1665–1669 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  255. Higgins, E. et al. Use of ruxolitinib to successfully treat chronic mucocutaneous candidiasis caused by gain-of-function signal transducer and activator of transcription 1 (STAT1) mutation. J. Allergy Clin. Immunol. 135, 551–553 (2015).

    Article  CAS  PubMed  Google Scholar 

  256. Meesilpavikkai, K. et al. Baricitinib treatment in a patient with a gain-of-function mutation in signal transducer and activator of transcription 1 (STAT1). J. Allergy Clin. Immunol. 142, 328–330 e322 (2018).

    Article  PubMed  Google Scholar 

  257. Rizzi, M. et al. Outcome of allogeneic stem cell transplantation in adults with common variable immunodeficiency. J. Allergy Clin. Immunol. 128, 1371–1374 e1372 (2011).

    Article  PubMed  Google Scholar 

  258. Wehr, C. et al. Multicenter experience in hematopoietic stem cell transplantation for serious complications of common variable immunodeficiency. J. Allergy Clin. Immunol. 135, 988–997.e986 (2015).

    Article  PubMed  Google Scholar 

  259. Fox, T. A. et al. Successful outcome following allogeneic hematopoietic stem cell transplantation in adults with primary immunodeficiency. Blood 131, 917–931 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. Olkinuora, H. et al. T cell regeneration in pediatric allogeneic stem cell transplantation. Bone Marrow Transpl. 39, 149–156 (2007).

    Article  CAS  Google Scholar 

  261. Lum, L. G. The kinetics of immune reconstitution after human marrow transplantation. Blood 69, 369–380 (1987).

    Article  CAS  PubMed  Google Scholar 

  262. Naik, S. et al. Adoptive immunotherapy for primary immunodeficiency disorders with virus-specific T lymphocytes. J. Allergy Clin. Immunol. 137, 1498–1505 e1491 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Castagnoli, R., Delmonte, O. M., Calzoni, E. & Notarangelo, L. D. Hematopoietic stem cell transplantation in primary immunodeficiency diseases: current status and future perspectives. Front. Pediatr. 7, 295 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  264. Marsh, R. A. et al. Practice pattern changes and improvements in hematopoietic cell transplantation for primary immunodeficiencies. J. Allergy Clin. Immunol. 142, 2004–2007 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  265. Gennery, A. R. et al. Transplantation of hematopoietic stem cells and long-term survival for primary immunodeficiencies in Europe: entering a new century, do we do better? J. Allergy Clin. Immunol. 126, 602–610.e601-611 (2010).

  266. Bezu, L., Chuang, A. W., Liu, P., Kroemer, G. & Kepp, O. Immunological effects of epigenetic modifiers. Cancers 11 (2019).

  267. Campos-Sanchez, E. & Martinez-Cano, J. Del Pino Molina, L., Lopez-Granados, E. & Cobaleda, C. Epigenetic deregulation in human primary immunodeficiencies. Trends Immunol. 40, 49–65 (2019).

    Article  CAS  PubMed  Google Scholar 

  268. Del Pino-Molina, L. et al. Impaired CpG demethylation in common variable immunodeficiency associates with B cell phenotype and proliferation rate. Front. Immunol. 10, 878 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  269. Titus, A. J., Gallimore, R. M., Salas, L. A. & Christensen, B. C. Cell-type deconvolution from DNA methylation: a review of recent applications. Hum. Mol. Genet. 26, R216–R224 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  270. Park, J. et al. Interferon signature in the blood in inflammatory common variable immune deficiency. PLoS ONE 8, e74893 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  271. Rodenburg, R. J. The functional genomics laboratory: functional validation of genetic variants. J. Inherit. Metab. Dis. 41, 297–307 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  272. Stavnezer-Nordgren, J., Kekish, O. & Zegers, B. J. Molecular defects in a human immunoglobulin kappa chain deficiency. Science 230, 458–461 (1985).

    Article  CAS  PubMed  Google Scholar 

  273. Bottaro, A., Cariota, U. & DeMarchi, M. & Carbonara, A.O. Pulsed-field electrophoresis screening for immunoglobulin heavy-chain constant-region (IGHC) multigene deletions and duplications. Am. J. Hum. Genet. 48, 745–756 (1991).

    CAS  PubMed  PubMed Central  Google Scholar 

  274. Ferrari, S. et al. Mutations of CD40 gene cause an autosomal recessive form of immunodeficiency with hyper IgM. Proc. Natl Acad. Sci. USA 98, 12614–12619 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  275. Zhang, K. H., Marsh, A. & Jordan, R. M.B. Identification of a phosphoinositide 3-kinase (PI-3K) p110 delta (PIK3CD) deficient individual. J. Clin. Immunol. 33, 673–674 (2013).

    Google Scholar 

  276. van Montfrans, J. M. et al. CD27 deficiency is associated with combined immunodeficiency and persistent symptomatic EBV viremia. J. Allergy Clin. Immunol. 129, 787–793.e786 (2012).

    Article  PubMed  CAS  Google Scholar 

  277. Salzer, E. et al. B-cell deficiency and severe autoimmunity caused by deficiency of protein kinase C delta. Blood 121, 3112–3116 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  278. Salzer, E. et al. Early-onset inflammatory bowel disease and common variable immunodeficiency-like disease caused by IL-21 deficiency. J. Allergy Clin. Immunol. 133, 1651–1659.e1612 (2014).

    Article  CAS  PubMed  Google Scholar 

  279. Kotlarz, D. et al. Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome. J. Exp. Med. 210, 433–443 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  280. Wiseman, D. H. et al. A novel syndrome of congenital sideroblastic anemia, B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD). Blood 122, 112–123 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  281. Zhou, Q. et al. A hypermorphic missense mutation in PLCG2, encoding phospholipase Cgamma2, causes a dominantly inherited autoinflammatory disease with immunodeficiency. Am. J. Hum. Genet. 91, 713–720 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors are indebted to A/Prof Robert Stirling, A/Prof Paul Cameron, Dr. Josh Chatelier, Ms. Pei M. Aui and Ms. Fiona Hore-Lacy for clinical, laboratory and administrative support, and to E/Prof Jennifer Rolland for critical reading of the manuscript. This work is supported by The Jeffrey Modell Foundation and the Australian National Health and Medical Research Council (NHMRC; Senior Research Fellowship 1117687 to M.C.v.Z.).

Author information

Authors and Affiliations

  1. Department of Immunology and Pathology, Central Clinical School, Monash University, Melbourne, VIC, Australia

    Emily S. J. Edwards, Robyn E. O’Hehir & Menno C. van Zelm

  2. The Jeffrey Modell Diagnostic and Research Centre for Primary Immunodeficiencies, Melbourne, VIC, Australia

    Emily S. J. Edwards, Julian J. Bosco, Samar Ojaimi, Robyn E. O’Hehir & Menno C. van Zelm

  3. Department of Allergy, Immunology and Respiratory Medicine, Central Clinical School, Monash University and Allergy, Asthma and Clinical Immunology Service, Alfred Hospital, Melbourne, VIC, Australia

    Julian J. Bosco, Robyn E. O’Hehir & Menno C. van Zelm

  4. Department of Infectious Diseases, Monash Health, Clayton, VIC, Australia

    Samar Ojaimi

  5. Centre for Inflammatory Diseases, Monash Health, Clayton, VIC, Australia

    Samar Ojaimi

  6. Department of Allergy and Immunology, Monash Health, Clayton, VIC, Australia

    Samar Ojaimi

Authors
  1. Emily S. J. Edwards
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Julian J. Bosco
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Samar Ojaimi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Robyn E. O’Hehir
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Menno C. van Zelm
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

E.S.J.E. and M.C.v.Z. conceptualized and wrote the manuscript. J.J.B., S.O., and R.E.O.H. provided critical feedback and commented on manuscript drafts. All authors approved the final version.

Corresponding author

Correspondence to Menno C. van Zelm.

Ethics declarations

Competing interests

The authors declare no competing interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Edwards, E.S.J., Bosco, J.J., Ojaimi, S. et al. Beyond monogenetic rare variants: tackling the low rate of genetic diagnoses in predominantly antibody deficiency. Cell Mol Immunol 18, 588–603 (2021). https://doi.org/10.1038/s41423-020-00520-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s41423-020-00520-8

Keywords

Search

Advanced search

Quick links