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Severe Combined Immunodeficiency due to RAG1 Deficiency

MedGen UID:
1784091
•Concept ID:
C5447328
•
Disease or Syndrome
Synonym: Severe Combined Immunodeficiency, T cell-Negative, B cell-Negative, RAG1

Definition

An inherited condition caused by mutation(s) in the RAG1 gene, encoding V(D)J recombination-activating protein 1. 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 RAG1 Deficiency

Professional guidelines

PubMed

A Decade Experience on Severe Combined Immunodeficiency Phenotype in Oman, Bridging to Newborn Screening.
Al Sukaiti N, Ahmed K, Alshekaili J, Al Kindi M, Cook MC, Farsi TA
Front Immunol 2020;11:623199. Epub 2021 Jan 15 doi: 10.3389/fimmu.2020.623199. PMID: 33519828Free PMC Article
Lentiviral vectors for the treatment of primary immunodeficiencies.
Farinelli G, Capo V, Scaramuzza S, Aiuti A
J Inherit Metab Dis 2014 Jul;37(4):525-33. Epub 2014 Mar 12 doi: 10.1007/s10545-014-9690-y. PMID: 24619149
A systematic analysis of recombination activity and genotype-phenotype correlation in human recombination-activating gene 1 deficiency.
Lee YN, Frugoni F, Dobbs K, Walter JE, Giliani S, Gennery AR, Al-Herz W, Haddad E, LeDeist F, Bleesing JH, Henderson LA, Pai SY, Nelson RP, El-Ghoneimy DH, El-Feky RA, Reda SM, Hossny E, Soler-Palacin P, Fuleihan RL, Patel NC, Massaad MJ, Geha RS, Puck JM, Palma P, Cancrini C, Chen K, Vihinen M, Alt FW, Notarangelo LD
J Allergy Clin Immunol 2014 Apr;133(4):1099-108. Epub 2013 Nov 28 doi: 10.1016/j.jaci.2013.10.007. PMID: 24290284Free PMC Article

Recent clinical studies

Etiology

Heterogeneity in RAG1 and RAG2 deficiency: 35 cases from a single-centre.
Karaatmaca B, Cagdas D, Esenboga S, Erman B, Tan C, Turul Ozgur T, Boztug K, van der Burg M, Sanal O, Tezcan I
Clin Exp Immunol 2024 Feb 7;215(2):160-176. doi: 10.1093/cei/uxad110. PMID: 37724703Free PMC Article
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
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

Diagnosis

NUDCD3 deficiency disrupts V(D)J recombination to cause SCID and Omenn syndrome.
Chen R, Lukianova E, van der Loeff IS, Spegarova JS, Willet JDP, James KD, Ryder EJ, Griffin H, IJspeert H, Gajbhiye A, Lamoliatte F, Marin-Rubio JL, Woodbine L, Lemos H, Swan DJ, Pintar V, Sayes K, Ruiz-Morales ER, Eastham S, Dixon D, Prete M, Prigmore E, Jeggo P, Boyes J, Mellor A, Huang L, van der Burg M, Engelhardt KR, Stray-Pedersen A, Erichsen HC, Gennery AR, Trost M, Adams DJ, Anderson G, Lorenc A, Trynka G, Hambleton S
Sci Immunol 2024 May 24;9(95):eade5705. doi: 10.1126/sciimmunol.ade5705. PMID: 38787962
Heterogeneity in RAG1 and RAG2 deficiency: 35 cases from a single-centre.
Karaatmaca B, Cagdas D, Esenboga S, Erman B, Tan C, Turul Ozgur T, Boztug K, van der Burg M, Sanal O, Tezcan I
Clin Exp Immunol 2024 Feb 7;215(2):160-176. doi: 10.1093/cei/uxad110. PMID: 37724703Free PMC Article
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
The immune system in hypertension.
Harrison DG
Trans Am Clin Climatol Assoc 2014;125:130-38; discussion 138-40. PMID: 25125726Free PMC Article
A systematic analysis of recombination activity and genotype-phenotype correlation in human recombination-activating gene 1 deficiency.
Lee YN, Frugoni F, Dobbs K, Walter JE, Giliani S, Gennery AR, Al-Herz W, Haddad E, LeDeist F, Bleesing JH, Henderson LA, Pai SY, Nelson RP, El-Ghoneimy DH, El-Feky RA, Reda SM, Hossny E, Soler-Palacin P, Fuleihan RL, Patel NC, Massaad MJ, Geha RS, Puck JM, Palma P, Cancrini C, Chen K, Vihinen M, Alt FW, Notarangelo LD
J Allergy Clin Immunol 2014 Apr;133(4):1099-108. Epub 2013 Nov 28 doi: 10.1016/j.jaci.2013.10.007. PMID: 24290284Free PMC Article

Therapy

Partial correction of immunodeficiency by lentiviral vector gene therapy in mouse models carrying Rag1 hypomorphic mutations.
Castiello MC, Di Verniere M, Draghici E, Fontana E, Penna S, Sereni L, Zecchillo A, Minuta D, Uva P, Zahn M, Gil-Farina I, Annoni A, Iaia S, Ott de Bruin LM, Notarangelo LD, Pike-Overzet K, Staal FJT, Villa A, Capo V
Front Immunol 2023;14:1268620. Epub 2023 Nov 13 doi: 10.3389/fimmu.2023.1268620. PMID: 38022635Free PMC Article
The immune system in hypertension.
Harrison DG
Trans Am Clin Climatol Assoc 2014;125:130-38; discussion 138-40. PMID: 25125726Free PMC Article
Atypical severe combined immunodeficiency caused by a novel homozygous mutation in Rag1 gene in a girl who presented with pyoderma gangrenosum: a case report and literature review.
Patiroglu T, Akar HH, Gilmour K, Ozdemir MA, Bibi S, Henriquez F, Burns SO, Unal E
J Clin Immunol 2014 Oct;34(7):792-5. Epub 2014 Aug 8 doi: 10.1007/s10875-014-0077-5. PMID: 25104208
Lentiviral vectors for the treatment of primary immunodeficiencies.
Farinelli G, Capo V, Scaramuzza S, Aiuti A
J Inherit Metab Dis 2014 Jul;37(4):525-33. Epub 2014 Mar 12 doi: 10.1007/s10545-014-9690-y. PMID: 24619149
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

A variant of RAG1 gene identified in severe combined immunodeficiency: a case report.
Zhang X, Kang X, Yang M, Cai Z, Song Y, Zhou X, Cao J, Wang C, Huang K, Peng Y, He J, Xiao Z
BMC Pediatr 2023 Feb 3;23(1):56. doi: 10.1186/s12887-022-03822-0. PMID: 36732712Free PMC Article
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
A Decade Experience on Severe Combined Immunodeficiency Phenotype in Oman, Bridging to Newborn Screening.
Al Sukaiti N, Ahmed K, Alshekaili J, Al Kindi M, Cook MC, Farsi TA
Front Immunol 2020;11:623199. Epub 2021 Jan 15 doi: 10.3389/fimmu.2020.623199. PMID: 33519828Free 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
RAG1 deficiency may present clinically as selective IgA deficiency.
Kato T, Crestani E, Kamae C, Honma K, Yokosuka T, Ikegawa T, Nishida N, Kanegane H, Wada T, Yachie A, Ohara O, Morio T, Notarangelo LD, Imai K, Nonoyama S
J Clin Immunol 2015 Apr;35(3):280-8. Epub 2015 Mar 6 doi: 10.1007/s10875-015-0146-4. PMID: 25739914

Clinical prediction guides

Transplantation after CD45-ADC corrects Rag1 immunodeficiency in congenic and haploidentical settings.
Pala F, Corsino C, Calzoni E, Villa A, Pittaluga S, Palchaudhuri R, Bosticardo M, Notarangelo LD
J Allergy Clin Immunol 2024 Jan;153(1):341-348.e3. Epub 2023 Aug 9 doi: 10.1016/j.jaci.2023.07.017. PMID: 37567393Free PMC Article
Partial correction of immunodeficiency by lentiviral vector gene therapy in mouse models carrying Rag1 hypomorphic mutations.
Castiello MC, Di Verniere M, Draghici E, Fontana E, Penna S, Sereni L, Zecchillo A, Minuta D, Uva P, Zahn M, Gil-Farina I, Annoni A, Iaia S, Ott de Bruin LM, Notarangelo LD, Pike-Overzet K, Staal FJT, Villa A, Capo V
Front Immunol 2023;14:1268620. Epub 2023 Nov 13 doi: 10.3389/fimmu.2023.1268620. PMID: 38022635Free PMC Article
A Decade Experience on Severe Combined Immunodeficiency Phenotype in Oman, Bridging to Newborn Screening.
Al Sukaiti N, Ahmed K, Alshekaili J, Al Kindi M, Cook MC, Farsi TA
Front Immunol 2020;11:623199. Epub 2021 Jan 15 doi: 10.3389/fimmu.2020.623199. PMID: 33519828Free 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
Thymocytes self-renewal: a major hope or a major threat?
Peaudecerf L, Krenn G, Gonçalves P, Vasseur F, Rocha B
Immunol Rev 2016 May;271(1):173-84. doi: 10.1111/imr.12408. PMID: 27088914

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