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Severe Combined Immunodeficiency due to RAG2 Deficiency

MedGen UID:
1785950
•Concept ID:
C5447329
•
Disease or Syndrome
Synonym: Severe Combined Immunodeficiency, T cell-Negative, B cell-Negative, RAG2

Definition

An autosomal recessive condition caused by mutation(s) in the RAG2 gene, encoding V(D)J recombination-activating protein 2. It is characterized by severe combined immunodeficiency that is both T-cell and B-cell negative. [from NCI]

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVSevere Combined Immunodeficiency due to RAG2 Deficiency

Professional guidelines

PubMed

Approaches to patients with variants in RAG genes: from diagnosis to timely treatment.
Bulkhi AA, Dasso JF, Schuetz C, Walter JE
Expert Rev Clin Immunol 2019 Oct;15(10):1033-1046. Epub 2019 Oct 10 doi: 10.1080/1744666X.2020.1670060. PMID: 31535575
Genetic Counseling in Primary Immunodeficiency Disorders: An Emerging Experience in Egypt.
El Hawary RE, Meshaal SS, Abd Elaziz DS, Elsharkawy MA, Alkady RS, Lotfy S, El-Sheikhah A, Hassan A, Galal NM, Boutros JA, Elmarsafy AM
Mol Diagn Ther 2017 Dec;21(6):677-684. doi: 10.1007/s40291-017-0297-5. PMID: 28900865
Advances in the understanding and treatment of human severe combined immunodeficiency.
Buckley RH
Immunol Res 2000;22(2-3):237-51. doi: 10.1385/IR:22:2-3:237. PMID: 11339359

Recent clinical studies

Etiology

Severe combined immunodeficiencies: Expanding the mutation spectrum in Turkey and identification of 12 novel variants.
Aykut A, Durmaz A, Karaca N, Gulez N, Genel F, Celmeli F, Ozturk G, Atay D, Aydogmus C, Kiykim A, Aksu G, Kutukculer N
Scand J Immunol 2022 Jun;95(6):e13163. Epub 2022 Mar 23 doi: 10.1111/sji.13163. PMID: 35303369
RAG deficiencies: Recent advances in disease pathogenesis and novel therapeutic approaches.
Bosticardo M, Pala F, Notarangelo LD
Eur J Immunol 2021 May;51(5):1028-1038. Epub 2021 Mar 22 doi: 10.1002/eji.202048880. PMID: 33682138Free PMC Article
Immune dysregulation in patients with RAG deficiency and other forms of combined immune deficiency.
Delmonte OM, Villa A, Notarangelo LD
Blood 2020 Feb 27;135(9):610-619. doi: 10.1182/blood.2019000923. PMID: 31942628Free PMC Article
Genetic mutations and immunological features of severe combined immunodeficiency patients in Iran.
Shahbazi Z, Yazdani R, Shahkarami S, Shahbazi S, Hamid M, Sadeghi-Shabestari M, Momen T, Aleyasin S, Esmaeilzadeh H, Darougar S, Delavari S, Mahdaviani SA, Ahanchian H, Behmanesh F, Kiaee F, Chavoshzade Z, Shariat M, Keramatipour M, Rezaei N, Abolhassani H, Parvaneh N, Mahdian R, Aghamohammadi A
Immunol Lett 2019 Dec;216:70-78. Epub 2019 Oct 4 doi: 10.1016/j.imlet.2019.10.001. PMID: 31589898
Approaches to patients with variants in RAG genes: from diagnosis to timely treatment.
Bulkhi AA, Dasso JF, Schuetz C, Walter JE
Expert Rev Clin Immunol 2019 Oct;15(10):1033-1046. Epub 2019 Oct 10 doi: 10.1080/1744666X.2020.1670060. PMID: 31535575

Diagnosis

The diagnosis of severe combined immunodeficiency: Implementation of the PIDTC 2022 Definitions.
Dvorak CC, Haddad E, Heimall J, Dunn E, Cowan MJ, Pai SY, Kapoor N, Satter LF, Buckley RH, O'Reilly RJ, Chandra S, Bednarski JJ, Williams O, Rayes A, Moore TB, Ebens CL, Davila Saldana BJ, Petrovic A, Chellapandian D, Cuvelier GDE, Vander Lugt MT, Caywood EH, Chandrakasan S, Eissa H, Goldman FD, Shereck E, Aquino VM, Desantes KB, Madden LM, Miller HK, Yu L, Broglie L, Gillio A, Shah AJ, Knutsen AP, Andolina JP, Joshi AY, Szabolcs P, Kapadia M, Martinez CA, Parrot RE, Sullivan KE, Prockop SE, Abraham RS, Thakar MS, Leiding JW, Kohn DB, Pulsipher MA, Griffith LM, Notarangelo LD, Puck JM
J Allergy Clin Immunol 2023 Feb;151(2):547-555.e5. Epub 2022 Nov 28 doi: 10.1016/j.jaci.2022.10.021. PMID: 36456360Free PMC Article
RAG deficiencies: Recent advances in disease pathogenesis and novel therapeutic approaches.
Bosticardo M, Pala F, Notarangelo LD
Eur J Immunol 2021 May;51(5):1028-1038. Epub 2021 Mar 22 doi: 10.1002/eji.202048880. PMID: 33682138Free PMC Article
Genetic mutations and immunological features of severe combined immunodeficiency patients in Iran.
Shahbazi Z, Yazdani R, Shahkarami S, Shahbazi S, Hamid M, Sadeghi-Shabestari M, Momen T, Aleyasin S, Esmaeilzadeh H, Darougar S, Delavari S, Mahdaviani SA, Ahanchian H, Behmanesh F, Kiaee F, Chavoshzade Z, Shariat M, Keramatipour M, Rezaei N, Abolhassani H, Parvaneh N, Mahdian R, Aghamohammadi A
Immunol Lett 2019 Dec;216:70-78. Epub 2019 Oct 4 doi: 10.1016/j.imlet.2019.10.001. PMID: 31589898
Approaches to patients with variants in RAG genes: from diagnosis to timely treatment.
Bulkhi AA, Dasso JF, Schuetz C, Walter JE
Expert Rev Clin Immunol 2019 Oct;15(10):1033-1046. Epub 2019 Oct 10 doi: 10.1080/1744666X.2020.1670060. PMID: 31535575
RAG Deficiency: Two Genes, Many Diseases.
Delmonte OM, Schuetz C, Notarangelo LD
J Clin Immunol 2018 Aug;38(6):646-655. Epub 2018 Jul 25 doi: 10.1007/s10875-018-0537-4. PMID: 30046960Free PMC Article

Therapy

Innovative Cell-Based Therapies and Conditioning to Cure RAG Deficiency.
Villa A, Capo V, Castiello MC
Front Immunol 2020;11:607926. Epub 2020 Nov 19 doi: 10.3389/fimmu.2020.607926. PMID: 33329604Free PMC Article
DNA recombination defects in Kuwait: Clinical, immunologic and genetic profile.
Al-Herz W, Massaad MJ, Chou J, Notarangelo LD, Geha RS
Clin Immunol 2018 Feb;187:68-75. Epub 2017 Oct 16 doi: 10.1016/j.clim.2017.10.006. PMID: 29051008Free PMC Article
Selective clinical and immune response of the oligoclonal autoreactive T cells in Omenn patients after cyclosporin A treatment.
Lev A, Simon AJ, Amariglio N, Rechavi G, Somech R
Clin Exp Immunol 2012 Feb;167(2):338-45. doi: 10.1111/j.1365-2249.2011.04508.x. PMID: 22236011Free PMC Article
Perspectives of gene therapy for primary immunodeficiencies.
Chinen J, Puck JM
Curr Opin Allergy Clin Immunol 2004 Dec;4(6):523-7. doi: 10.1097/00130832-200412000-00008. PMID: 15640693
Molecular defects in human severe combined immunodeficiency and approaches to immune reconstitution.
Buckley RH
Annu Rev Immunol 2004;22:625-55. doi: 10.1146/annurev.immunol.22.012703.104614. PMID: 15032591

Prognosis

Severe combined immunodeficiencies: Expanding the mutation spectrum in Turkey and identification of 12 novel variants.
Aykut A, Durmaz A, Karaca N, Gulez N, Genel F, Celmeli F, Ozturk G, Atay D, Aydogmus C, Kiykim A, Aksu G, Kutukculer N
Scand J Immunol 2022 Jun;95(6):e13163. Epub 2022 Mar 23 doi: 10.1111/sji.13163. PMID: 35303369
Vasculitis as a Major Morbidity Factor in Patients With Partial RAG Deficiency.
Geier CB, Farmer JR, Foldvari Z, Ujhazi B, Steininger J, Sleasman JW, Parikh S, Dilley MA, Pai SY, Henderson L, Hazen M, Neven B, Moshous D, Sharapova SO, Mihailova S, Yankova P, Naumova E, Özen S, Byram K, Fernandez J, Wolf HM, Eibl MM, Notarangelo LD, Calabrese LH, Walter JE
Front Immunol 2020;11:574738. Epub 2020 Oct 21 doi: 10.3389/fimmu.2020.574738. PMID: 33193364Free PMC Article
A Large Cohort of RAG1/2-Deficient SCID Patients-Clinical, Immunological, and Prognostic Analysis.
Greenberg-Kushnir N, Lee YN, Simon AJ, Lev A, Marcus N, Abuzaitoun O, Somech R, Stauber T
J Clin Immunol 2020 Jan;40(1):211-222. Epub 2019 Dec 14 doi: 10.1007/s10875-019-00717-1. PMID: 31838659
Genetic mutations and immunological features of severe combined immunodeficiency patients in Iran.
Shahbazi Z, Yazdani R, Shahkarami S, Shahbazi S, Hamid M, Sadeghi-Shabestari M, Momen T, Aleyasin S, Esmaeilzadeh H, Darougar S, Delavari S, Mahdaviani SA, Ahanchian H, Behmanesh F, Kiaee F, Chavoshzade Z, Shariat M, Keramatipour M, Rezaei N, Abolhassani H, Parvaneh N, Mahdian R, Aghamohammadi A
Immunol Lett 2019 Dec;216:70-78. Epub 2019 Oct 4 doi: 10.1016/j.imlet.2019.10.001. PMID: 31589898
Recombination activity of human recombination-activating gene 2 (RAG2) mutations and correlation with clinical phenotype.
Tirosh I, Yamazaki Y, Frugoni F, Ververs FA, Allenspach EJ, Zhang Y, Burns S, Al-Herz W, Noroski L, Walter JE, Gennery AR, van der Burg M, Notarangelo LD, Lee YN
J Allergy Clin Immunol 2019 Feb;143(2):726-735. Epub 2018 Jun 18 doi: 10.1016/j.jaci.2018.04.027. PMID: 29772310Free PMC Article

Clinical prediction guides

iPSC-Based Modeling of RAG2 Severe Combined Immunodeficiency Reveals Multiple T Cell Developmental Arrests.
Themeli M, Chhatta A, Boersma H, Prins HJ, Cordes M, de Wilt E, Farahani AS, Vandekerckhove B, van der Burg M, Hoeben RC, Staal FJT, Mikkers HMM
Stem Cell Reports 2020 Feb 11;14(2):300-311. Epub 2020 Jan 16 doi: 10.1016/j.stemcr.2019.12.010. PMID: 31956083Free PMC Article
Genetic mutations and immunological features of severe combined immunodeficiency patients in Iran.
Shahbazi Z, Yazdani R, Shahkarami S, Shahbazi S, Hamid M, Sadeghi-Shabestari M, Momen T, Aleyasin S, Esmaeilzadeh H, Darougar S, Delavari S, Mahdaviani SA, Ahanchian H, Behmanesh F, Kiaee F, Chavoshzade Z, Shariat M, Keramatipour M, Rezaei N, Abolhassani H, Parvaneh N, Mahdian R, Aghamohammadi A
Immunol Lett 2019 Dec;216:70-78. Epub 2019 Oct 4 doi: 10.1016/j.imlet.2019.10.001. PMID: 31589898
Recombination activity of human recombination-activating gene 2 (RAG2) mutations and correlation with clinical phenotype.
Tirosh I, Yamazaki Y, Frugoni F, Ververs FA, Allenspach EJ, Zhang Y, Burns S, Al-Herz W, Noroski L, Walter JE, Gennery AR, van der Burg M, Notarangelo LD, Lee YN
J Allergy Clin Immunol 2019 Feb;143(2):726-735. Epub 2018 Jun 18 doi: 10.1016/j.jaci.2018.04.027. PMID: 29772310Free PMC Article
RAG Deficiency: Two Genes, Many Diseases.
Delmonte OM, Schuetz C, Notarangelo LD
J Clin Immunol 2018 Aug;38(6):646-655. Epub 2018 Jul 25 doi: 10.1007/s10875-018-0537-4. PMID: 30046960Free PMC Article
Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency.
Walter JE, Rosen LB, Csomos K, Rosenberg JM, Mathew D, Keszei M, Ujhazi B, Chen K, Lee YN, Tirosh I, Dobbs K, Al-Herz W, Cowan MJ, Puck J, Bleesing JJ, Grimley MS, Malech H, De Ravin SS, Gennery AR, Abraham RS, Joshi AY, Boyce TG, Butte MJ, Nadeau KC, Balboni I, Sullivan KE, Akhter J, Adeli M, El-Feky RA, El-Ghoneimy DH, Dbaibo G, Wakim R, Azzari C, Palma P, Cancrini C, Capuder K, Condino-Neto A, Costa-Carvalho BT, Oliveira JB, Roifman C, Buchbinder D, Kumanovics A, Franco JL, Niehues T, Schuetz C, Kuijpers T, Yee C, Chou J, Masaad MJ, Geha R, Uzel G, Gelman R, Holland SM, Recher M, Utz PJ, Browne SK, Notarangelo LD
J Clin Invest 2015 Nov 2;125(11):4135-48. Epub 2015 Oct 12 doi: 10.1172/JCI80477. PMID: 26457731Free PMC Article

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