Journal of Clinical Immunology

, Volume 35, Issue 2, pp 119–124 | Cite as

Identification of Patients with RAG Mutations Previously Diagnosed with Common Variable Immunodeficiency Disorders

  • David Buchbinder
  • Rebecca Baker
  • Yu Nee Lee
  • Juan Ravell
  • Yu Zhang
  • Joshua McElwee
  • Diane Nugent
  • Emily M. Coonrod
  • Jacob D. Durtschi
  • Nancy H. Augustine
  • Karl V. Voelkerding
  • Krisztian Csomos
  • Lindsey Rosen
  • Sarah Browne
  • Jolan E. Walter
  • Luigi D. Notarangelo
  • Harry R. Hill
  • Attila Kumánovics
Original Research

Abstract

Purpose

Combined immunodeficiency (CID) presents a unique challenge to clinicians. Two patients presented with the prior clinical diagnosis of common variable immunodeficiency (CVID) disorder marked by an early age of presentation, opportunistic infections, and persistent lymphopenia. Due to the presence of atypical clinical features, next generation sequencing was applied documenting RAG deficiency in both patients.

Methods

Two different genetic analysis techniques were applied in these patients including whole exome sequencing in one patient and the use of a gene panel designed to target genes known to cause primary immunodeficiency disorders (PIDD) in a second patient. Sanger dideoxy sequencing was used to confirm RAG1 mutations in both patients.

Results

Two young adults with a history of recurrent bacterial sinopulmonary infections, viral infections, and autoimmune disease as well as progressive hypogammaglobulinemia, abnormal antibody responses, lymphopenia and a prior diagnosis of CVID disorder were evaluated. Compound heterozygous mutations in RAG1 (1) c256_257delAA, p86VfsX32 and (2) c1835A>G, pH612R were documented in one patient. Compound heterozygous mutations in RAG1 (1) c.1566G>T, p.W522C and (2) c.2689C>T, p. R897X) were documented in a second patient post-mortem following a fatal opportunistic infection.

Conclusion

Astute clinical judgment in the evaluation of patients with PIDD is necessary. Atypical clinical findings such as early onset, granulomatous disease, or opportunistic infections should support the consideration of atypical forms of late onset CID secondary to RAG deficiency. Next generation sequencing approaches provide powerful tools in the investigation of these patients and may expedite definitive treatments.

Keywords

RAG1 RAG deficiency primary immunodeficiency severe combined immune deficiency common variable immunodeficiency disorder exome sequencing gene panel 

Supplementary material

10875_2014_121_MOESM1_ESM.doc (225 kb)
ESM 1(DOC 225 kb)

References

  1. 1.
    Felgentreff, Perez-Becker R, Speckmann C, Schwarz K, et al. Clinical and immunological manifestations of patients with atypical severe combined immunodeficiency. Clin Immunol. 2011;141(1):73–82.CrossRefPubMedGoogle Scholar
  2. 2.
    Conley ME, Casanova JL. Discovery of single-gene inborn errors of immunity by next generation sequencing. Curr Opin Immunol. 2014;30C:17–23.CrossRefGoogle Scholar
  3. 3.
    Lee YN, Frugoni F, Dobbs K, Walter JE, et al. A systematic analysis of recombination activity and genotype-phenotype correlation in human recombination-activating gene 1 deficiency. J Allergy Clin Immunol. 2014;133(4):1099–108.CrossRefPubMedGoogle Scholar
  4. 4.
    Schwarz K, Gauss GH, Ludwig L, Pannicke U, et al. RAG mutations in human B cell-negative SCID. Science. 1996;274(5284):97–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Chen K, Wu W, Mathew D, Zhang Y, et al. Autoimmunity due to RAG deficiency and estimated disease incidence in RAG1/2 mutations. J Allergy Clin Immunol. 2014;133(3):880–2.e10.Google Scholar
  6. 6.
    Sharapova SO, Migas A, Guryanova I, Aleshkevich S, et al. Late-onset combined immune deficiency associated to skin granuloma due to heterozygous compound mutations in RAG1 gene in a 14 years old male. Hum Immunol. 2013;74(1):118–22.CrossRefGoogle Scholar
  7. 7.
    Pieper K, Rizzi M, Speletas M, Smulski CR, et al. A common single nucleotide polymorphism impairs B-cell activating factor receptor’s multimerization, contributing to common variable immunodeficiency. J Allergy Clin Immunol. 2014;133(4):1222–5.CrossRefPubMedGoogle Scholar
  8. 8.
    Kumaki S, Villa A, Asada H, Kawai S, et al. Identification of anti-herpes simplex virus antibody-producing B cells in a patient with an atypical RAG1 immunodeficiency. Blood. 2001;98(5):1464–8.CrossRefPubMedGoogle Scholar
  9. 9.
    Villa A, Bozzi F, Sobacchi C, Strina D, et al. Prenatal diagnosis of RAG-deficient Omenn syndrome. Prenat Diagn. 2000;20(1):56–9.CrossRefPubMedGoogle Scholar
  10. 10.
    De Ravin SS, Cowen EW, Zarember KA, Whiting-Theobald NL, et al. Hypomorphic RAG mutations can cause destructive midline granulomatous disease. Blood. 2010;116(8):1263–71.CrossRefPubMedCentralPubMedGoogle Scholar
  11. 11.
    Malphettes M, Gerard L, Carmagnat M, Mouillot G, et al. Late-onset combined immune deficiency: a subset of common variable immunodeficiency with severe T cell defect. Clin Infect Dis. 2009;49(9):1329–38.CrossRefPubMedGoogle Scholar
  12. 12.
    Rose CD. Granulomatous inflammation: The overlap of immune deficiency and inflammation. Best Pract Res Clin Rheumatol. 2014;28(2):191–212.CrossRefPubMedGoogle Scholar
  13. 13.
    de Villartay JP, Lim A, Al-Mousa H, Dupont A, et al. A novel immunodeficiency associated with hypomorphic RAG1 mutations and CMV infection. J Clin Invest. 2005;115(11):3291–9.CrossRefPubMedCentralPubMedGoogle Scholar
  14. 14.
    Ehl S, Schwarz K, Enders A, Duffner U, et al. A variant of SCID with specific immune responses and predominance of gamma delta T cells. J Clin Invest. 2005;115(11):3140–8.CrossRefPubMedCentralPubMedGoogle Scholar
  15. 15.
    Karaca NE, Aksu G, Genel F, Gulez N, et al. Diverse phenotypic and genotypic presentation of RAG1 mutations in two cases with SCID. Clin Exp Med. 2009;9(4):339–42.CrossRefPubMedGoogle Scholar
  16. 16.
    Schuetz C, Huck K, Gudowius S, Megahed M, et al. An immunodeficiency disease with RAG mutations and granulomas. N Engl J Med. 2008;358(19):2030–8.CrossRefPubMedGoogle Scholar
  17. 17.
    Reiff A, Bassuk AG, Church JA, Campbell E, et al. Exome sequencing reveals RAG1 mutations in a child with autoimmunity and sterile chronic multifocal osteomyelitis evolving into disseminated granulomatous disease. J Clin Immunol. 2013;33(8):1289–92.CrossRefPubMedGoogle Scholar
  18. 18.
    Kuijpers TW, Ijspeert H, van Leeuwen EM, Jansen MH, et al. Idiopathic CD4+ T lymphopenia without autoimmunity or granulomatous disease in the slipstream of RAG mutations. Blood. 2011;117(22):5892–6.CrossRefPubMedGoogle Scholar
  19. 19.
    Abraham RS, Recher M, Giliani S, Walter JE, et al. Adult-onset manifestation of idiopathic T-cell lymphopenia due to a heterozygous RAG1 mutation. J Allergy Clin Immunol. 2013;131(5):1421–3.CrossRefPubMedCentralPubMedGoogle Scholar
  20. 20.
    Gathmann B, Mahlaoui N, CEREDIH, Gerard L, et al. Clinical picture and treatment of 2212 patients with common variable immunodeficiency. J Allergy Clin Immunol. 2014;134(1):116–26.CrossRefPubMedGoogle Scholar
  21. 21.
    Abolhassani H, Wang N, Aghamohammadi A, Rezaei N, et al. A hypomorphic recombination-activating gene 1 (RAG1) mutation resulting in a phenotype resembling common variable immunodeficiency. J Allergy Clin Immunol. 2014.Google Scholar
  22. 22.
    Nijman IJ, van Montfrans JM, Hoogstraat M, Boes ML, et al. Targeted next-generation sequencing: a novel diagnostic tool for primary immunodeficiencies. J Allergy Clin Immunol. 2014;133(2):529–34.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • David Buchbinder
    • 1
    • 12
  • Rebecca Baker
    • 2
  • Yu Nee Lee
    • 3
  • Juan Ravell
    • 2
  • Yu Zhang
    • 4
  • Joshua McElwee
    • 5
  • Diane Nugent
    • 1
  • Emily M. Coonrod
    • 7
  • Jacob D. Durtschi
    • 7
  • Nancy H. Augustine
    • 7
    • 8
  • Karl V. Voelkerding
    • 7
    • 8
  • Krisztian Csomos
    • 11
  • Lindsey Rosen
    • 2
  • Sarah Browne
    • 2
  • Jolan E. Walter
    • 6
    • 11
  • Luigi D. Notarangelo
    • 6
  • Harry R. Hill
    • 7
    • 8
    • 9
    • 10
  • Attila Kumánovics
    • 7
    • 8
  1. 1.Pediatrics / HematologyCHOC Children’s Hospital—UC IrvineOrangeUSA
  2. 2.Laboratory of Clinical Infectious DiseasesNIAID, NIHBethesdaUSA
  3. 3.Division of ImmunologyBoston Children’s Hospital Harvard Medical SchoolBostonUSA
  4. 4.Laboratory of Host DefensesNational Institutes of Allergy and Infectious Diseases, NIHBethesdaUSA
  5. 5.Merck Research LaboratoriesMerck & Co. Inc.BostonUSA
  6. 6.Division of ImmunologyBoston Children’s HospitalBostonUSA
  7. 7.ARUP Institute for Clinical and Experimental PathologySalt Lake CityUSA
  8. 8.Department of PathologyUniversity of Utah School of MedicineSalt Lake CityUSA
  9. 9.Department of Internal MedicineUniversity of Utah School of MedicineSalt Lake CityUSA
  10. 10.Department of PediatricsUniversity of Utah School of MedicineSalt Lake CityUSA
  11. 11.Pediatric Allergy & Immunology and the Center for Immunology and Inflammatory Diseases, Massachusetts General HospitalHarvard Medical SchoolBostonUSA
  12. 12.Division of HematologyCHOC Children’s HospitalOrangeUSA

Personalised recommendations