Molecular Diagnosis of Severe Combined Immunodeficiency—Identification of IL2RG, JAK3, IL7R, DCLRE1C, RAG1, and RAG2 Mutations in a Cohort of Chinese and Southeast Asian Children
First Online: 24 December 2010 Received: 07 September 2010 Accepted: 08 November 2010 DOI:
10.1007/s10875-010-9489-z Cite this article as: Lee, P.P.W., Chan, K., Chen, T. et al. J Clin Immunol (2011) 31: 281. doi:10.1007/s10875-010-9489-z Abstract
Severe combined immunodeficiencies (SCID) are a group of rare inherited disorders with profound defects in T cell and B cell immunity. From 2005 to 2010, our unit performed testing for
IL2RG, JAK3, IL7R, RAG1, RAG2, DCLRE1C, LIG4, AK2, and ZAP70 mutations in 42 Chinese and Southeast Asian infants with SCID adopting a candidate gene approach, based on patient’s gender, immune phenotype, and inheritance pattern. Mutations were identified in 26 patients, including IL2RG ( n = 19), IL7R ( n = 2), JAK3 ( n = 2), RAG1 ( n = 1), RAG2 ( n = 1), and DCLRE1C ( n = 1). Among 12 patients who underwent hematopoietic stem cell transplantation, eight patients survived. Complications and morbidities during transplant period were significant, especially disseminated bacillus Calmette–Guérin disease which was often difficult to control. This is the first cohort study on SCID in the Chinese and Southeast Asian population, based on a multi-centered collaborative research network. The foremost issue is service provision for early detection, diagnosis, management, and definitive treatment for patients with SCID. National management guidelines for SCID should be established, and research into an efficient platform for genetic diagnosis is needed. Keyword Severe combined immunodeficiency SCID molecular diagnosis genetics Chinese Asian Electronic supplementary material
The online version of this article (doi:
) contains supplementary material, which is available to authorized users. 10.1007/s10875-010-9489-z
An erratum to this article can be found online at
Lipstein EA, Vorono S, Browning MF, Green NS, Kemper AR, Knapp AA, et al. Systematic evidence review of newborn screening and treatment of severe combined immunodeficiency. Pediatrics. 2010;25:e1226–35.
Buckley RH. Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution. Annu Rev Immunol. 2004;22:625–55.
Niehues T, Perez-Becker R, Schuetz C. More than just SCID—the phenotypic range of combined immunodeficiencies associated with mutations in the recombinase activating genes (RAG) 1 and 2. Clin Immunol. 2010;135:183–92.
Notarangelo LD, Fischer A, Geha RS, Casanova JL, Chapel H, Conley ME, et al. International Union of Immunological Societies Expert Committee on Primary Immunodeficiencies. Primary immunodeficiencies: 2009 update. J Allergy Clin Immunol. 2009;124:1161–78.
Liston A, Enders A, Siggs OM. Unravelling the association of partial T-cell immunodeficiency and immune dysregulation. Nat Rev Immunol. 2008;8:545–58.
Shiow LR, Paris K, Akana MC, Cyster JG, Sorensen RU, Puck JM. Severe combined immunodeficiency (SCID) and attention deficit hyperactivity disorder (ADHD) associated with a Coronin-1A mutation and a chromosome 16p11.2 deletion. Clin Immunol. 2009;131:24–30.
Shiow LR, Roadcap DW, Paris K, Watson SR, Grigorova IL, Lebet T, et al. The actin regulator coronin 1A is mutant in a thymic egress-deficient mouse strain and in a patient with severe combined immunodeficiency. Nat Immunol. 2008;9:1307–15.
Pannicke U, Hönig M, Hess I, Friesen C, Holzmann K, Rump EM, et al. Reticular dysgenesis (aleukocytosis) is caused by mutations in the gene encoding mitochondrial adenylate kinase 2. Nat Genet. 2009;41:101–5.
Lagresle-Peyrou C, Six EM, Picard C, Rieux-Laucat F, Michel V, Ditadi A, et al. Human adenylate kinase 2 deficiency causes a profound hematopoietic defect associated with sensorineural deafness. Nat Genet. 2009;41:106–11.
Conley ME, Notarangelo LD, Etzioni A. Diagnostic criteria for primary immunodeficiencies. Representing PAGID (Pan-American Group for Immunodeficiency) and ESID (European Society for Immunodeficiencies). Clin Immunol. 1999;93:190–7.
Fairbanks LD, Goday A, Morris GS, Brolsma MF, Simmonds HA, Gibson T. Rapid determination of purine enzyme activity in intact and lysed cells using high performance liquid chromatography. J Chromatogr. 1983;276:427.
Simmonds HA, Fairbanks LD, Morris GS, Webster DR, Harley EH. Altered erythrocyte nucleotide patterns are characteristic of inherited disorders of purine and pyrimidine metabolism. Clin Chim Acta. 1988;171:97.
Lipman M, Breen R. Immune reconstitution inflammatory syndrome in HIV. Curr Opin Infect Dis. 2006;19:20–5.
Playford EG, Bansal AS, Looke DF, Whitby M, Hogan PG. Hypercalcaemia and elevated 1, 25(OH)(2)D(3) levels associated with disseminated
infection in AIDS. J Infect. 2001;42:157–8.
Lawn SD, Macallan DC. Hypercalcemia: a manifestation of immune reconstitution complicating tuberculosis in an HIV-infected person. Clin Infect Dis. 2004;38:154–5.
Lee PP, Lau YL. Primary immunodeficiencies: “new” disease in an old country. Cell Mol Immunol. 2009;6:397–406.
Aytekin C, Yuksek M, Dogu F, Yagmurlu A, Yildiran A, Fitoz S, et al. An unconditioned bone marrow transplantation in a child with purine nucleoside phosphorylase deficiency and its unique complication. Pediatr Transplant. 2008;12:479–82.
Bernatowska EA, Wolska-Kusnierz B, Pac M, Kurenko-Deptuch M, Zwolska Z, Casanova JL, et al. Disseminated bacillus Calmette–Guérin infection and immunodeficiency. Emerg Infect Dis. 2007;13:799–801.
Ikincioğullari A, Doğu F, Ciftci E, Unal E, Ertem M, Reisli I, et al. An intensive approach to the treatment of disseminated BCG infection in a SCID patient. Bone Marrow Transplant. 2002;30:45–7.
McKenzie RH, Roux P. Disseminated BCG infection following bone marrow transplantation for X-linked severe combined immunodeficiency. Pediatr Dermatol. 2000;17:208–12.
Skinner R, Appleton AL, Sprott MS, Barer MR, Magee JG, Darbyshire PJ, et al. Disseminated BCG infection in severe combined immunodeficiency presenting with severe anaemia and associated with gross hypersplenism after bone marrow transplantation. Bone Marrow Transplant. 1996;17:877–80.
Heyderman RS, Morgan G, Levinsky RJ, Strobel S. Successful bone marrow transplantation and treatment of BCG infection in two patients with severe combined immunodeficiency. Eur J Pediatr. 1991;150:477–80.
Minegishi M, Tsuchiya S, Imaizumi M, Yamaguchi Y, Goto Y, Tamura M, et al. Successful transplantation of soy bean agglutinin-fractionated, histoincompatible, maternal marrow in a patient with severe combined immunodeficiency and BCG infection. Eur J Pediatr. 1985;143:291–4.
Gonzalez B, Moreno S, Burdach R, Valenzuela MT, Henriquez A, Ramos MI, et al. Clinical presentation of bacillus Calmette–Guérin infections in patients with immunodeficiency syndromes. Pediatr Infect Dis J. 1989;8:201–6.
Talbot EA, Perkins MD, Silva SF, Frothingham R. Disseminated bacille Calmette–Guérin disease after vaccination: case report and review. Clin Infect Dis. 1997;24:1139–46.
Lotte A, Wasz-Höckert O, Poisson N, Dumitrescu N, Verron M, Couvet E. BCG complications. Estimates of the risks among vaccinated subjects and statistical analysis of their main characteristics. Adv Tuberc Res. 1984;21:107–93.
Reichenbach J, Rosenzweig S, Döffinger R, Dupuis S, Holland SM, Casanova JL. Mycobacterial diseases in primary immunodeficiencies. Curr Opin Allergy Clin Immunol. 2001;1:503–11.
Yeganeh M, Heidarzade M, Pourpak Z, Parvaneh N, Rezaei N, Gharagozlou M, et al. Severe combined immunodeficiency: a cohort of 40 patients. Pediatr Allergy Immunol. 2008;19:303–6.
Jean-Philippe P, Freedman A, Chang MW, Steinberg SP, Gershon AA, LaRussa PS, et al. Severe varicella caused by varicella-vaccine strain in a child with significant T-cell dysfunction. Pediatrics. 2007;120:e1345–9.
Patel NC, Hertel PM, Estes MK, de la Morena M, Petru AM, Noroski LM, et al. Vaccine-acquired rotavirus in infants with severe combined immunodeficiency. N Engl J Med. 2010;362:314–9.
Uygungil B, Bleesing JJ, Risma KA, McNeal MM, Rothenberg ME. Persistent rotavirus vaccine shedding in a new case of severe combined immunodeficiency: a reason to screen. J Allergy Clin Immunol. 2010;125:270–1.
Comeau AM, Hale JE, Pai SY, et al. Guideline for implementation of population-based newborn screening for severe combined immunodeficiency. J Inherit Metab Dis. 2010;33:S273–81. doi:
Gennery AR, Slatter MA, Grandin L, Taupin P, Cant AJ, Veys P, 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. 2010;126:602–10.
Dvorak CC, Cowan MJ. Hematopoietic stem cell transplantation for primary immunodeficiency disease. Bone Marrow Transplant. 2008;41:119–26.
Buckley RH, Schiff SE, Schiff RI, Markert L, Williams LW, Roberts JL, et al. Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. N Engl J Med. 1999;340:508–16.
Lau YL, Kwong YL, Lee AC, Chiu EK, Ha SY, Chan CF, et al. Mixed chimerism following bone marrow transplantation for severe combined immunodeficiency: a study by DNA fingerprinting and simultaneous immunophenotyping and fluorescence in situ hybridisation. Bone Marrow Transplant. 1995;15:971–6.
Buckley RH. B-cell function in severe combined immunodeficiency after stem cell or gene therapy: a review. J Allergy Clin Immunol. 2010;125:790–7.
Satwani P, Cooper N, Rao K, Veys P, Amrolia P. Reduced intensity conditioning and allogeneic stem cell transplantation in childhood malignant and non-malignant diseases. Bone Marrow Transplant. 2008;41:173–82.
Buckley RH. The multiple causes of human SCID. J Clin Invest. 2004;114:1409–11.
Villa A, Notarangelo LD, Roifman CM. Omenn syndrome: inflammation in leaky severe combined immunodeficiency. J Allergy Clin Immunol. 2008;122:1082–6.
Lebet T, Chiles R, Hsu AP, Mansfield ES, Warrington JA, Puck JM. Mutations causing severe combined immunodeficiency: detection with a custom resequencing microarray. Genet Med. 2008;10:575–85.
Griffith LM, Cowan MJ, Notarangelo LD, Puck JM, Buckley RH, Candotti F, et al. Improving cellular therapy for primary immune deficiency diseases: recognition, diagnosis, and management. J Allergy Clin Immunol. 2009;124:1152–60. e12.
CrossRef PubMed Copyright information
© Springer Science+Business Media, LLC 2010