Journal of Clinical Immunology

, Volume 35, Issue 2, pp 119–124

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

DOI: 10.1007/s10875-014-0121-5

Cite this article as:
Buchbinder, D., Baker, R., Lee, Y.N. et al. J Clin Immunol (2015) 35: 119. doi:10.1007/s10875-014-0121-5

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)

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