A newly found homozygous mutation in recombination activating gene 1 in a patient with leaky severe combined immunodeficiency disorder

  • Fereshteh Salari
  • Fatemeh Zaremehrjardi
  • Saba Arshi
  • Mohammad Hassan Bemanian
  • Morteza Fallahpour
  • Sima Shokri
  • Farhad Seif
  • Masoud MovahediEmail author
  • Mohammad NabaviEmail author
Short Communication


The recombination activating genes, including RAG1 and RAG2, are essential for V(D)J somatic recombination in lymphocytes. Leaky severe combined immunodeficiency disorder (SCID) is characterized by normal or intermediate T cells and normal to absent B cells associated with partial T cell and B cell dysfunction. We present a newly found RAG1 deficiency in a 21-year-old boy with leaky SCID. Immunoglobulin levels, flow cytometry, and whole exome sequencing (WES) were evaluated. Flow cytometric analysis revealed a decreased number of CD3+, CD4+, and CD8+ T cells, and B cells whereas NK cell counts were normal. Immunoglobulin levels were also decreased. The WES revealed a newly found homozygous mutation of RAG1 gene (NM_000448: exon 2: c.C2275T). Atypical features, including leukopenia, candidiasis, and low lymphocyte counts in patients with late-onset combined immunodeficiency disorders (CID) such as leaky SCID due to RAG1 deficiency may result in misdiagnosis and inadequate therapy instead of adopting the curative hematopoietic stem cell transplantation in these patients.


RAG deficiency SCID Whole exome sequencing Mutation 


Author contributions

FS gathered the data. FS and FS wrote the manuscript. SA, MB, MN, MF, FZ, SS, and MM contributed to the patient management. All authors edited and approved the final version of the paper.


No funding was provided for this work.

Compliance with ethical standards

Conflict of interest

The authors declare they have no conflict of interests.

Ethical approval

The present case report was approved by the Ethics Committee of the Iran University of Medical sciences (Iran).

Informed consent

Written informed consent was obtained from the patient.


  1. 1.
    Schatz DG, Swanson PC (2011) V(D)J recombination: mechanisms of initiation. Annu Rev Genet 45:167–202CrossRefGoogle Scholar
  2. 2.
    Geier CB, Piller A, Linder A, Sauerwein KM, Eibl MM, Wolf HM (2015) Leaky RAG deficiency in adult patients with impaired antibody production against bacterial polysaccharide antigens. PLoS ONE 10(7):e0133220CrossRefGoogle Scholar
  3. 3.
    Alt FW, Zhang Y, Meng F-L, Guo C, Schwer B (2013) Mechanisms of programmed DNA lesions and genomic instability in the immune system. Cell 152(3):417–429CrossRefGoogle Scholar
  4. 4.
    IJspeert H, Driessen GJ, Moorhouse MJ, Hartwig NG, Wolska-Kusnierz B, Kalwak K et al (2014) Similar recombination-activating gene (RAG) mutations result in similar immunobiological effects but in different clinical phenotypes. J Allergy Clin Immunol 133(4):1124–1133 (e1) CrossRefGoogle Scholar
  5. 5.
    Karaca NE, Aksu G, Genel F, Gulez N, Can S, Aydinok Y et al (2009) Diverse phenotypic and genotypic presentation of RAG1 mutations in two cases with SCID. Clin Exp Med 9(4):339CrossRefGoogle Scholar
  6. 6.
    Lee YN, Frugoni F, Dobbs K, Tirosh I, Du L, Ververs FA et al (2016) Characterization of T and B cell repertoire diversity in patients with RAG deficiency. Sci Immunol 1(6):eaah6109CrossRefGoogle Scholar
  7. 7.
    Meshaal SS, El Hawary RE, Abd Elaziz D, Eldash A, Alkady R, Lotfy S et al (2019) Phenotypical heterogeneity in RAG-deficient patients from a highly consanguineous population. Clin Exp Immunol 195(2):202–212CrossRefGoogle Scholar
  8. 8.
    Shearer WT, Dunn E, Notarangelo LD, Dvorak CC, Puck JM, Logan BR et al (2014) Establishing diagnostic criteria for severe combined immunodeficiency disease (SCID), leaky SCID, and Omenn syndrome: the Primary Immune Deficiency Treatment Consortium experience. J Allergy Clin Immunol 133(4):1092–1098CrossRefGoogle Scholar
  9. 9.
    Seif F, Khoshmirsafa M, Mousavi M, Beshkar P, Rafeian-Kopaei M, Bagheri N et al (2014) Interleukin-21 receptor might be a novel therapeutic target for the treatment of rheumatoid arthritis. J Exp Clin Med 6(2):57–61CrossRefGoogle Scholar
  10. 10.
    Zhang J, Quintal L, Atkinson A, Williams B, Grunebaum E, Roifman CM (2005) Novel RAG1 mutation in a case of severe combined immunodeficiency. Pediatrics 116(3):e445–e449CrossRefGoogle Scholar
  11. 11.
    Khan TA, Iqbal A, Rahman H, Cabral-Marques O, Ishfaq M, Muhammad N (2017) Novel RAG1 mutation and the occurrence of mycobacterial and Chromobacterium violaceum infections in a case of leaky SCID. Microb Pathog 109:114–119CrossRefGoogle Scholar
  12. 12.
    Nabavi M, Arshi S, Bemanian M, Aghamohammadi A, Mansouri D, Hedayat M et al (2016) Long-term follow-up of ninety eight Iranian patients with primary immune deficiency in a single tertiary centre. Allergol Immunopathol 44(4):322–330CrossRefGoogle Scholar
  13. 13.
    Arshi S, Nabavi M, Bemanian MH, Shakeri R, Taghvaei B, Ghalebaghi B et al (2016) Phenotyping and follow up of forty-seven Iranian patients with common variable immunodeficiency. Allergol Immunopathol 44(3):226–231CrossRefGoogle Scholar
  14. 14.
    Noordzij JG, de Bruin-Versteeg S, Verkaik NS, Vossen JM, de Groot R, Bernatowska E et al (2002) The immunophenotypic and immunogenotypic B-cell differentiation arrest in bone marrow of RAG-deficient SCID patients corresponds to residual recombination activities of mutated RAG proteins. Blood 100(6):2145–2152Google Scholar
  15. 15.
    Corneo B, Moshous D, Güngör T, Wulffraat N, Philippet P, Le Deist F et al (2001) Identical mutations in RAG1 or RAG2 genes leading to defective V (D) J recombinase activity can cause either TB–severe combined immune deficiency or Omenn syndrome. Blood 97(9):2772–2776CrossRefGoogle Scholar
  16. 16.
    Schuetz C, Pannicke U, Jacobsen E-M, Burggraf S, Albert MH, Hönig M et al (2014) Lesson from hypomorphic recombination-activating gene (RAG) mutations: why asymptomatic siblings should also be tested. J Allergy Clin Immunol 133(4):1211–1215 (e2) CrossRefGoogle Scholar
  17. 17.
    Dorna MB, Barbosa PF, Rangel-Santos A, Csomos K, Ujhazi B, Dasso JF et al (2019) Combined immunodeficiency with late-onset progressive hypogammaglobulinemia and normal B cell count in a patient with RAG2 deficiency. Front Pediatr 7:122CrossRefGoogle Scholar
  18. 18.
    Pasic S, Djuricic S, Ristic G, Slavkovic B (2009) Recombinase-activating gene 1 immunodeficiency: different immunological phenotypes in three siblings. Acta Paediatr 98(6):1062–1064CrossRefGoogle Scholar
  19. 19.
    Shearer WT, Rosenblatt HM, Gelman RS, Oyomopito R, Plaeger S, Stiehm ER et al (2003) Lymphocyte subsets in healthy children from birth through 18 years of age: the Pediatric AIDS Clinical Trials Group P1009 study. J Allergy Clin Immunol 112(5):973–980CrossRefGoogle Scholar

Copyright information

© Springer Nature B.V. 2019

Authors and Affiliations

  • Fereshteh Salari
    • 1
  • Fatemeh Zaremehrjardi
    • 1
  • Saba Arshi
    • 1
  • Mohammad Hassan Bemanian
    • 1
  • Morteza Fallahpour
    • 1
  • Sima Shokri
    • 1
  • Farhad Seif
    • 2
    • 3
  • Masoud Movahedi
    • 4
    Email author
  • Mohammad Nabavi
    • 1
    Email author
  1. 1.Department of Allergy & Clinical ImmunologyIran University of Medical SciencesTehranIran
  2. 2.Academic Center for Education, Culture, and ResearchTehran University of Medical SciencesTehranIran
  3. 3.Neuroscience Research CenterIran University of Medical SciencesTehranIran
  4. 4.Immunology Asthma, and Allergy Research InstituteTehran University of Medical SciencesTehranIran

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