Advertisement

Genetics of CVID

  • Vasssilios Lougaris
  • Alessandro PlebaniEmail author
Chapter
Part of the Rare Diseases of the Immune System book series (RDIS)

Abstract

Common variable immunodeficiency (CVID) is the most common symptomatic primary humoral immunodeficiency. Hallmarks of the disease include hypogammaglobulinemia, recurrent infections, autoimmune manifestations, and increased lymphoma risk. Although the first cases were reported in the early 1950s, it took more than 50 years before the first genetic cause of CVID was described. Since then, and thanks to the advances in the field of genetic research, several genetic causes have been identified for CVID, offering thus a better understanding of the pathogenesis of this disorder and explaining its great clinical variability.

In this chapter, we present an overview of the genetic findings related to CVID that apply still to a limited number of affected patients.

Keywords

CVID B cells T cells Lymphoma Autoimmunity Infections 

References

  1. 1.
    Cunningham-Rundles C. The many faces of common variable immunodeficiency. Hematology Am Soc Hematol Educ Program. 2012;2012:301–5.PubMedPubMedCentralGoogle Scholar
  2. 2.
    Bruton OC, Apt L, Gitlin D, Janeway AC. Absence of serum gamma globulins. AMA Am J Dis Child. 1952;84(5):632–6.PubMedGoogle Scholar
  3. 3.
    Grimbacher B, Hutloff A, Schlesier M, Glocker E, Warnatz K, Dräger R, Eibel H, Fischer B, Schäffer AA, Mages HW, Kroczek RA, Peter HH. Homozygous loss of ICOS is associated with adult-onset common variable immunodeficiency. Nat Immunol. 2003;4(3):261–8.CrossRefGoogle Scholar
  4. 4.
    Warnatz K, Bossaller L, Salzer U, Skrabl-Baumgartner A, Schwinger W, van der Burg M, van Dongen JJ, Orlowska-Volk M, Knoth R, Durandy A, Draeger R, Schlesier M, Peter HH, Grimbacher B. Human ICOS deficiency abrogates the germinal center reaction and provides a monogenic model for common variable immunodeficiency. Blood. 2006;107(8):3045–52.CrossRefGoogle Scholar
  5. 5.
    Castigli E, Wilson SA, Garibyan L, Rachid R, Bonilla F, Schneider L, Geha RS. TACI is mutant in common variable immunodeficiency and IgA deficiency. Nat Genet. 2005;37:829–34.CrossRefGoogle Scholar
  6. 6.
    Salzer U, Chapel HM, Webster ADB, Pan-Hammarstrom Q, Schmitt-Graeff A, Schlesier M, Peter HH, Rockstroh JK, Schneider P, Schaffer AA, Hammarstrom L, Grimbacher B. Mutations in TNFRSF13B encoding TACI are associated with common variable immunodeficiency in humans. Nat Genet. 2005;37:820–8.CrossRefGoogle Scholar
  7. 7.
    Yan M, Wang H, Chan B, Roose-Girma M, Erickson S, Baker T, Tumas D, Grewal IS, Dixit VM. Activation and accumulation of B cells in TACI-deficient mice. Nat Immun. 2001;2:638–43.CrossRefGoogle Scholar
  8. 8.
    Pan-Hammarstrom Q, Salzer U, Du L, Bjorkander J, Cunningham-Rundles C, Nelson DL, Bacchelli C, Gaspar HB, Offer S, Behrens TW, Grimbacher B, Hammarstrom L. Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency. Nat Genet. 2007;39:429–30.CrossRefGoogle Scholar
  9. 9.
    Castigli E, Wilson S, Garibyan L, Rachid R, Bonilla F, Schneider L, Morra M, Curran J, Geha R. Reexamining the role of TACI coding variants in common variable immunodeficiency and selective IgA deficiency. Nat Genet. 2007;39:430–1.CrossRefGoogle Scholar
  10. 10.
    Lougaris V, Gallizzi R, Vitali M, Baronio M, Salpietro A, Bergbreiter A, Salzer U, Badolato R, Plebani A. A novel compound heterozygous TACI mutation in an autosomal recessive common variable immunodeficiency (CVID) family. Hum Immunol. 2012;73(8):836–9.CrossRefGoogle Scholar
  11. 11.
    Salzer U, Bacchelli C, Buckridge S, Pan-Hammarstrom Q, Jennings S, Lougaris V, Bergbreiter A, Hagena T, Birmelin J, Plebani A, Webster ADB, Peter H-H, et al. Relevance of biallelic versus monoallelic TNFRSF13B mutations in distinguishing disease-causing from risk-increasing TNFRSF13B variants in antibody deficiency syndromes. Blood. 2009;113:1967–76.CrossRefGoogle Scholar
  12. 12.
    Losi CG, Silini A, Fiorini C, Soresina A, Meini A, Ferrari S, Notarangelo LD, Lougaris V, Plebani A. Mutational analysis of human BAFF receptor TNFRSF13C (BAFF-R) in patients with common variable immunodeficiency. J Clin Immunol. 2005;25(5):496–502.CrossRefGoogle Scholar
  13. 13.
    Pieper K, Rizzi M, Speletas M, Smulski CR, Sic H, Kraus H, Salzer U, Fiala GJ, Schamel WW, Lougaris V, Plebani A, Hammarstrom L, Recher M, Germenis AE, Grimbacher B, Warnatz K, Rolink AG, Schneider P, Notarangelo LD, Eibel H. A common single nucleotide polymorphism impairs B-cell activating factor receptor’s multimerization, contributing to common variable immunodeficiency. J Allergy Clin Immunol. 2014;133:1222–5.CrossRefGoogle Scholar
  14. 14.
    Warnatz K, Salzer U, Rizzi M, Fischer B, Gutenberger S, Böhm J, Kienzler AK, Pan-Hammarström Q, Hammarström L, Rakhmanov M, Schlesier M, Grimbacher B, Peter HH, Eibel H. B-cell activating factor receptor deficiency is associated with an adult-onset antibody deficiency syndrome in humans. Proc Natl Acad Sci U S A. 2009;106(33):13945–50.CrossRefGoogle Scholar
  15. 15.
    Losi CG, Salzer U, Gatta R, Lougaris V, Cattaneo G, Meini A, Soresina A, Grimbacher B, Plebani A. Mutational analysis of human BLyS in patients with common variable immunodeficiency. J Clin Immunol. 2006;26(4):396–9.CrossRefGoogle Scholar
  16. 16.
    Salzer U, Neumann C, Thiel J, Woellner C, Pan-Hammarström Q, Lougaris V, Hagena T, Jung J, Birmelin J, Du L, Metin A, Webster DA, Plebani A, Moschese V, Hammarström L, Schäffer AA, Grimbacher B. Screening of functional and positional candidate genes in families with common variable immunodeficiency. BMC Immunol. 2008;7(9):3.CrossRefGoogle Scholar
  17. 17.
    van Zelm MC, Reisli I, van der Burg M, Castaño D, van Noesel CJ, van Tol MJ, Woellner C, Grimbacher B, Patiño PJ, van Dongen JJ, Franco JL. An antibody-deficiency syndrome due to mutations in the CD19 gene. N Engl J Med. 2006;354(18):1901–12.CrossRefGoogle Scholar
  18. 18.
    Kanegane H, Agematsu K, Futatani T, Sira MM, Suga K, Sekiguchi T, van Zelm MC, Miyawaki T. Novel mutations in a Japanese patient with CD19 deficiency. Genes Immun. 2007;8(8):663–70.CrossRefGoogle Scholar
  19. 19.
    Kuijpers TW, Bende RJ, Baars PA, Grummels A, Derks IA, Dolman KM, Beaumont T, Tedder TF, van Noesel CJ, Eldering E, van Lier RA. CD20 deficiency in humans results in impaired T cell-independent antibody responses. J Clin Invest. 2010;120(1):214–22.CrossRefGoogle Scholar
  20. 20.
    van Zelm MC, Smet J, Adams B, Mascart F, Schandené L, Janssen F, Ferster A, Kuo CC, Levy S, van Dongen JJ, van der Burg M. CD81 gene defect in humans disrupts CD19 complex formation and leads to antibody deficiency. J Clin Invest. 2010;120(4):1265–74.CrossRefGoogle Scholar
  21. 21.
    Thiel J, Kimmig L, Salzer U, Grudzien M, Lebrecht D, Hagena T, Draeger R, Völxen N, Bergbreiter A, Jennings S, Gutenberger S, Aichem A, Illges H, Hannan JP, Kienzler AK, Rizzi M, Eibel H, Peter HH, Warnatz K, Grimbacher B, Rump JA, Schlesier M. Genetic CD21 deficiency is associated with hypogammaglobulinemia. J Allergy Clin Immunol. 2012;129(3):801–10.CrossRefGoogle Scholar
  22. 22.
    Salzer E, Santos-Valente E, Klaver S, Ban SA, Emminger W, Prengemann NK, Garncarz W, Müllauer L, Kain R, Boztug H, Heitger A, Arbeiter K, Eitelberger F, Seidel MG, Holter W, Pollak A, Pickl WF, Förster-Waldl E, Boztug K. B-cell deficiency and severe autoimmunity caused by deficiency of protein kinase C δ. Blood. 2013;121(16):3112–6.CrossRefGoogle Scholar
  23. 23.
    Kuehn HS, Niemela JE, Rangel-Santos A, Zhang M, Pittaluga S, Stoddard JL, Hussey AA, Evbuomwan MO, Priel DA, Kuhns DB, Park CL, Fleisher TA, Uzel G, Oliveira JB. Loss-of-function of the protein kinase C δ (PKCδ) causes a B-cell lymphoproliferative syndrome in humans. Blood. 2013;121(16):3117–25.CrossRefGoogle Scholar
  24. 24.
    Belot A, Kasher PR, Trotter EW, Foray AP, Debaud AL, Rice GI, Szynkiewicz M, Zabot MT, Rouvet I, Bhaskar SS, Daly SB, Dickerson JE, Mayer J, O'Sullivan J, Juillard L, Urquhart JE, Fawdar S, Marusiak AA, Stephenson N, Waszkowycz B, Beresford MW, Biesecker LG, Black GCM, René C, Eliaou JF, Fabien N, Ranchin B, Cochat P, Gaffney PM, Rozenberg F, Lebon P, Malcus C, Crow YJ, Brognard J, Bonnefoy N. Protein kinase cδ deficiency causes mendelian systemic lupus erythematosus with B cell-defective apoptosis and hyperproliferation. Arthritis Rheum. 2013;65(8):2161–71.CrossRefGoogle Scholar
  25. 25.
    Angulo I, Vadas O, Garçon F, Banham-Hall E, Plagnol V, Leahy TR, et al. Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage. Science. 2013;342(6160):866–71.CrossRefGoogle Scholar
  26. 26.
    Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U, Avery DT, Moens L, Cannons JL, Biancalana M, Stoddard J, Ouyang W, Frucht DM, Rao VK, Atkinson TP, Agharahimi A, Hussey AA, Folio LR, Olivier KN, Fleisher TA, Pittaluga S, Holland SM, Cohen JI, Oliveira JB, Tangye SG, Schwartzberg PL, Lenardo MJ, Uzel G. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110d result in T cell senescence and human immunodeficiency. Nat Immunol. 2014;15(1):88–97.CrossRefGoogle Scholar
  27. 27.
    Kracker S, Curtis J, Ibrahim MA, Sediva A, Salisbury J, Campr V, Debré M, Edgar JD, Imai K, Picard C, Casanova JL, Fischer A, Nejentsev S, Durandy A. Occurrence of B-cell lymphomas in patients with activated phosphoinositide 3-kinase δ syndrome. J Allergy Clin Immunol. 2014;134(1):233–6.CrossRefGoogle Scholar
  28. 28.
    Deau MC, Heurtier L, Frange P, Suarez F, Bole-Feysot C, Nitschke P, et al. A human immunodeficiency caused by mutations in the PIK3R1 gene. J Clin Invest. 2014;124(9):3923–8.CrossRefGoogle Scholar
  29. 29.
    Lucas CL, Zhang Y, Venida A, Wang Y, Hughes J, McElwee J, et al. Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K. J Exp Med. 2014;211(13):2537–47.CrossRefGoogle Scholar
  30. 30.
    Lougaris V, Faletra F, Lanzi G, Vozzi D, Marcuzzi A, Valencic E, Piscianz E, Bianco A, Girardelli M, Baronio M, Loganes C, Fasth A, Salvini F, Trizzino A, Moratto D, Facchetti F, Giliani S, Plebani A, Tommasini A. Altered germinal center reaction and abnormal B cell peripheral maturation in PI3KR1-mutated patients presenting with HIGM-like phenotype. Clin Immunol. 2015;159(1):33–6.CrossRefGoogle Scholar
  31. 31.
    Lougaris V, Patrizi O, Baronio M, Tabellini G, Tampella G, Lanzi G, Salvini F, Trizzino A, Parolini S, Plebani A. p85a is an intrinsic regulator of human natural killer effector functions. J Allergy Clin Immunol. 2016;138(2):605–608.e3.  https://doi.org/10.1016/j.jaci.2016.01.026.CrossRefPubMedGoogle Scholar
  32. 32.
    Ruiz-Garcia R, Vargas-Hernandez A, Chinn IK, Angelo LS, Cao TN, Coban-Akdemir Z, Jhangiani SN, Meng Q, Forbes LR, Muzny DM, Allende LM, Ehlayel MS, Gibbs RA, Lupski JR, Uzel G, Orange JS, Mace EM. Mutations in PI3K110D cause impaired natural killer cell function partially rescued by rapamycin treatment. J Allergy Clin Immunol. 2018;142:605–617.e7.  https://doi.org/10.1016/j.jaci.2017.11.042.CrossRefPubMedGoogle Scholar
  33. 33.
    Wang HY, Ma CA, Zhao Y, Fan X, Zhou Q, Edmonds P, Uzel G, Oliveira JB, Orange J, Jain A. Antibody deficiency associated with an inherited autosomal dominat mutation in TWEAK. Proc Natl Acad Sci U S A. 2013;110(13):5127–32.CrossRefGoogle Scholar
  34. 34.
    Lopez-Herrera G, Tampella G, Pan-Hammarström Q, Herholz P, Trujillo-Vargas CM, Phadwal K, Simon AK, Moutschen M, Etzioni A, Mory A, Srugo I, Melamed D, Hultenby K, Liu C, Baronio M, Vitali M, Philippet P, Dideberg V, Aghamohammadi A, Rezaei N, Enright V, Du L, Salzer U, Eibel H, Pfeifer D, Veelken H, Stauss H, Lougaris V, Plebani A, Gertz EM, Schäffer AA, Hammarström L, Grimbacher B. Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity. Am J Hum Genet. 2012;90(6):986–1001.CrossRefGoogle Scholar
  35. 35.
    Burns SO, Zenner HL, Plagnol V, Curtis J, Mok K, Eisenhut M, Kumararatne D, Doffinger R, Thrasher AJ, Nejentsev S. LRBA gene deletion in a patient presenting with autoimmunity without hypogammaglobulinemia. J Allergy Clin Immunol. 2012;130(6):1428–32.CrossRefGoogle Scholar
  36. 36.
    Gamez-Diaz L, August D, Stepensky P, Revel-Vilk S, Seidel MG, Noriko M, Morio T, AJJ W, Blessing J, Van de Veerdonk F, Feuchtinger T, Kanariou M, Schmitt-Graeff A, Jung S, Seneviratne S, Burns S, Belohradsky BH, Rezaei N, Bakthiar S, Speckmann C, Jordan M, Grimbacher B. The extended phenotype of LPS-responsive beige-like anchor protein (LRBA) deficiency. J Allergy Clin Immunol. 2016;137(1):223–30.CrossRefGoogle Scholar
  37. 37.
    Backthiar S, Gamez-Diaz L, Jarish A, Soerensen J, Grimbacher B, Belohradsky B, Keller KM, Rietschel C, Klingebiel T, Koletzko S, Albert MH, Bader P. Treatment of infantile inflammatory bowel disease and autoimmunity by allogeneic stem cell transplantation in LPS-responsive beige-like anchor deficiency. Front Immunol. 2017;8:52.Google Scholar
  38. 38.
    Chen K, Coonrod EM, Kumanovics A, Franks ZF, Durtschi JD, Margraf RL, Wu W, Heikal NM, Augustine NH, Ridge PG, Hill HR, Jorde LB, Weyrich AS, Zimmerman GA, Gundlapalli AV, Bohnsack JF, Voelkerding KV. Germline mutations in NFKB2 implicate the noncanonical NF-kB pathway in the pathogenesis of common variable immunodeficiency. Am J Hum Genet. 2013;93(5):812–24.CrossRefGoogle Scholar
  39. 39.
    Lindsley AW, Qian Y, Valencia CA, Shah K, Zhang K, Assasd A. Combined immune deficiency in a patient with a novel NFKB2 mutation. J Clin Immunol. 2014;34(8):910–5.CrossRefGoogle Scholar
  40. 40.
    Lee CE, Fulcher DA, Whittle B, Chand R, Fewings N, Field M, Andrews D, Goodnow CC, Cook MC. Autosomal dominant B cell deficiency with alopecia due to a mutation in NFKB2 that results in non processable p100. Blood. 2014;124(19):2964–72.CrossRefGoogle Scholar
  41. 41.
    Lougaris V, Tabellini G, Vitali M, Baronio M, Patrizi O, Tampella G, Biasini A, Moratto D, Parolini S, Plebani A. Defective natural killer-cell cytotoxic activity in NFKB2-mutated CVID-like disease. J Allergy Clin Immunol. 2015;135:1641–3.CrossRefGoogle Scholar
  42. 42.
    Fliegauf M, Bryant VL, Frede N, Slade C, Woon ST, Lehnert K, Winzer S, Bulashevska A, Scerri T, Leung E, Jordan A, Keller B, de Vries E, Cao H, Yang F, Schäffer AA, Warnatz K, Browett P, Douglass J, Ameratunga RV, van der Meer JW, Grimbacher B. Haploinsufficiency of the NF-kB1 subunit p50 in common variable immunodeficiency. Am J Hum Genet. 2015;97(3):389–403.CrossRefGoogle Scholar
  43. 43.
    Lougaris V, Moratto D, Baronio M, Tampella G, van der Meer JW, Badolato R, Fliegauf M, Plebani A. Early and late B-cell developmental impairment in nuclear factor kappa B, subunit 1-mutated common variable immunodeficiency disease. J Allergy Clin Immunol. 2017;139:349–352.e1.  https://doi.org/10.1016/j.jaci.2016.05.045.CrossRefPubMedGoogle Scholar
  44. 44.
    Schipp C, Nabhani S, Bienemann K, Simanovsky N, Kfir-Erenfeld S, Assayag-Asherie N, Oommen PT, Revel-Vilk S, Honscheid A, Gombert M, Ginzel S, Schaffer D, Laws HJ, Yenenof E, Fleckenstein B, Borkhardt A, Stepensky P, Fischer U. Specific antibody deficiency and autoinflammatory disease extend the clinical and immunological spectrum of NFKB1 loss-of-function mutations in humans. Haematologica. 2016;101(10):e392–6.CrossRefGoogle Scholar
  45. 45.
    Boztug H, Hirschmugl T, Holter W, Lakatos K, Kager L, Trapin D, Pickl W, Forster-Wadl E, Boztug K. Nf-kB1 haploinsufficiency causing immunodeficiency and EBV-driven lymphoproliferation. J Clin Immunol. 2016;36(6):533–40.CrossRefGoogle Scholar
  46. 46.
    Lougaris V, Patrizi O, Baronio M, Tabellini G, Tampella G, Damiati E, Frede N, van der Meer JW, Fliegauf M, Grimbacher B, Parolini S, Plebani A. NFKB1 regulates human NK cell maturation and effector functions. Clin Immunol. 2017;175:99–108.  https://doi.org/10.1016/j.clim.2016.11.012.CrossRefPubMedGoogle Scholar
  47. 47.
    Schubert D, Bode C, Kenefeck R, Hou TZ, Wing JB, Kennedy A, Bulashevska A, Petersen BS, Schäffer AA, Grüning BA, Unger S, Frede N, Baumann U, Witte T, Schmidt RE, Dueckers G, Niehues T, Seneviratne S, Kanariou M, Speckmann C, Ehl S, Rensing-Ehl A, Warnatz K, Rakhmanov M, Thimme R, Hasselblatt P, Emmerich F, Cathomen T, Backofen R, Fisch P, Seidl M, May A, Schmitt-Graeff A, Ikemizu S, Salzer U, Franke A, Sakaguchi S, Walker LSK, Sansom DM, Grimbacher B. Autosomal dominant immune dysregulation in humans with CTLA4 mutations. Nat Med. 2014;20(12):1410–6.  https://doi.org/10.1038/nm.3746.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Kuehn HS, Ouyang W, Lo B, Deenick EK, Niemela JE, Avery DT, Schickel JN, Tran DQ, Stoddard J, Zhang Y, Frucht DM, Dumitriu B, Scheinberg P, Folio LR, Frein CA, Price S, Koh C, Heller T, Seroogy CM, Huttenlocher A, Rao VK, Su HC, Kleiner D, Notarangelo LD, Rampertaap Y, Olivier KN, McElwee J, Hughes J, Pittaluga S, Oliveira JB, Meffre E, Fleisher TA, Holland SM, Lenardo MJ, Tangye SG, Uzel G. Immune dysregulation in human subjects with heterozygous germline mutations in CTLA-4. Science. 2014;345(6204):1623–7.  https://doi.org/10.1126/science.1255904.CrossRefPubMedPubMedCentralGoogle Scholar
  49. 49.
    Miska J, Lui JB, Toomer KH, Devarajan P, Cai X, Houghton J, Lopez DM, Abreu MT, Wang G, Chen Z. Initiation of inflammatory tumorigenesis by CTLA4 insufficiency due to type 2 cytokines. J Exp Med. 2018;215:841–58.CrossRefGoogle Scholar
  50. 50.
    Lo B, Zhang K, Lu W, Zheng L, Zhang Q, Kanellopoulou C, Zhang Y, Liu Z, Fritz JM, Marsh R, Husami A, Kissell D, Nortman S, Chaturvedi V, Haines H, Young LR, Mo J, Filipovich AH, Bleesing JJ, Mustillo P, Stephens M, Rueda CM, Chougnet CA, Hoebe K, McElwee J, Hughes JD, Karakoc-Aydiner E, Matthews HF, Price S, Su HC, Rao VK, Lenardo MJ, Jordan MD. Autoimmune disease: patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy. Science. 2015;349(6246):436–40.CrossRefGoogle Scholar
  51. 51.
    Alroqi FJ, Charbonnier LM, Baris S, Kiykim A, Chou J, Platt CD, Algassim A, Keles S, Al Saud BK, Alkuraya FS, Jordan M, Geha RS, Chatila TA. Exaggerated follicular helper T cell responses in patients with LRBA deficiency caused by failure of CTLA4-mediated regulation. J Allergy Clin Immunol. 2018;141:1050–1059.e10.  https://doi.org/10.1016/j.jaci.2017.05.022.CrossRefPubMedGoogle Scholar
  52. 52.
    Sekine H, Ferreira RC, Pan-Hammarström Q, Graham RR, Ziemba B, de Vries SS, Liu J, Hippen K, Koeuth T, Ortmann W, Iwahori A, Elliott MK, Offer S, Skon C, Du L, Novitzke J, Lee AT, Zhao N, Tompkins JD, Altshuler D, Gregersen PK, Cunningham-Rundles C, Harris RS, Her C, Nelson DL, Hammarström L, Gilkeson GS, Behrens TW. Role for Msh5 in the regulation of Ig class switch recombination. Proc Natl Acad Sci U S A. 2007;104(17):7193–8.CrossRefGoogle Scholar
  53. 53.
    Sobacchi C, Marrella V, Rucci F, Vezzoni P, Villa A. RAG-dependent primary immunodeficiencies. Hum Mutat. 2006;27(12):1174–84. ReviewCrossRefGoogle Scholar
  54. 54.
    Abolhassani H, Wang N, Aghamohammadi A, Rezaei N, Lee YN, Frugoni F, Notarangelo LD, Pan-Hammarström Q, Hammarström L. A hypomorphic recombination-activating gene 1 (RAG1) mutation resulting in a phenotype resembling common variable immunodeficiency. J Allergy Clin Immunol. 2014;134(6):1375–80.  https://doi.org/10.1016/j.jaci.2014.04.042.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Buchbinder D, Baker R, Lee YN, Ravell J, Zhang Y, McElwee J, Nugent D, Coonrod EM, Durtschi JD, Augustine NH, Voelkerding KV, Csomos K, Rosen L, Browne S, Walter JE, Notarangelo LD, Hill HR, Kumánovics A. Identification of patients with RAG mutations previously diagnosed with common variable immunodeficiency disorders. J Clin Immunol. 2015;35(2):119–24.  https://doi.org/10.1007/s10875-014-0121-5.CrossRefPubMedGoogle Scholar
  56. 56.
    Schröder C, Baerlecken NT, Pannicke U, Dörk T, Witte T, Jacobs R, Stoll M, Schwarz K, Grimbacher B, Schmidt RE, Atschekzei F. Evaluation of RAG1 mutations in an adult with combined immunodeficiency and progressive multifocal leukoencephalopathy. Clin Immunol. 2017;179:1–7.  https://doi.org/10.1016/j.clim.2016.12.013.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Pediatrics Clinic and Institute for Molecular Medicine A. Nocivelli, Department of Clinical and Experimental SciencesUniversity of Brescia, ASST Spedali Civili of BresciaBresciaItaly

Personalised recommendations