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Hypomorphic RAG1 Deficiency

MedGen UID:
926467
•Concept ID:
C4288935
•
Disease or Syndrome

Definition

A condition of decreased or absent presence or activity of V(D)J recombination-activating protein 1. Deficiency of this protein is associated with Omenn syndrome, severe combined immunodeficiency, b cell-negative, combined cellular and humoral immune defects with granulomas, and alpha/beta T-cell lymphopenia with gamma/delta T-cell expansion, severe cytomegalovirus infection, and autoimmunity. [from NCI]

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVHypomorphic RAG1 Deficiency

Recent clinical studies

Etiology

Hypomorphic RAG deficiency: impact of disease burden on survival and thymic recovery argues for early diagnosis and HSCT.
Schuetz C, Gerke J, Ege M, Walter J, Kusters M, Worth A, Kanakry JA, Dimitrova D, Wolska-Kuśnierz B, Chen K, Unal E, Karakukcu M, Pashchenko O, Leiding J, Kawai T, Amrolia PJ, Berghuis D, Buechner J, Buchbinder D, Cowan MJ, Gennery AR, Güngör T, Heimall J, Miano M, Meyts I, Morris EC, Rivière J, Sharapova SO, Shaw PJ, Slatter M, Honig M, Veys P, Fischer A, Cavazzana M, Moshous D, Schulz A, Albert MH, Puck JM, Lankester AC, Notarangelo LD, Neven B
Blood 2023 Feb 16;141(7):713-724. doi: 10.1182/blood.2022017667. PMID: 36279417Free PMC Article
Clinical, Immunological, and Molecular Variability of RAG Deficiency: A Retrospective Analysis of 22 RAG Patients.
Cifaldi C, Rivalta B, Amodio D, Mattia A, Pacillo L, Di Cesare S, Chiriaco M, Ursu GM, Cotugno N, Giancotta C, Manno EC, Santilli V, Zangari P, Federica G, Palumbo G, Merli P, Palma P, Rossi P, Di Matteo G, Locatelli F, Finocchi A, Cancrini C
J Clin Immunol 2022 Jan;42(1):130-145. Epub 2021 Oct 18 doi: 10.1007/s10875-021-01130-3. PMID: 34664192Free 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
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
Phenotypical heterogeneity in RAG-deficient patients from a highly consanguineous population.
Meshaal SS, El Hawary RE, Abd Elaziz DS, Eldash A, Alkady R, Lotfy S, Mauracher AA, Opitz L, Pachlopnik Schmid J, van der Burg M, Chou J, Galal NM, Boutros JA, Geha R, Elmarsafy AM
Clin Exp Immunol 2019 Feb;195(2):202-212. Epub 2018 Nov 4 doi: 10.1111/cei.13222. PMID: 30307608Free PMC Article

Diagnosis

Hypomorphic RAG deficiency: impact of disease burden on survival and thymic recovery argues for early diagnosis and HSCT.
Schuetz C, Gerke J, Ege M, Walter J, Kusters M, Worth A, Kanakry JA, Dimitrova D, Wolska-Kuśnierz B, Chen K, Unal E, Karakukcu M, Pashchenko O, Leiding J, Kawai T, Amrolia PJ, Berghuis D, Buechner J, Buchbinder D, Cowan MJ, Gennery AR, Güngör T, Heimall J, Miano M, Meyts I, Morris EC, Rivière J, Sharapova SO, Shaw PJ, Slatter M, Honig M, Veys P, Fischer A, Cavazzana M, Moshous D, Schulz A, Albert MH, Puck JM, Lankester AC, Notarangelo LD, Neven B
Blood 2023 Feb 16;141(7):713-724. doi: 10.1182/blood.2022017667. PMID: 36279417Free PMC Article
Clinical, Immunological, and Molecular Variability of RAG Deficiency: A Retrospective Analysis of 22 RAG Patients.
Cifaldi C, Rivalta B, Amodio D, Mattia A, Pacillo L, Di Cesare S, Chiriaco M, Ursu GM, Cotugno N, Giancotta C, Manno EC, Santilli V, Zangari P, Federica G, Palumbo G, Merli P, Palma P, Rossi P, Di Matteo G, Locatelli F, Finocchi A, Cancrini C
J Clin Immunol 2022 Jan;42(1):130-145. Epub 2021 Oct 18 doi: 10.1007/s10875-021-01130-3. PMID: 34664192Free 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
Phenotypical heterogeneity in RAG-deficient patients from a highly consanguineous population.
Meshaal SS, El Hawary RE, Abd Elaziz DS, Eldash A, Alkady R, Lotfy S, Mauracher AA, Opitz L, Pachlopnik Schmid J, van der Burg M, Chou J, Galal NM, Boutros JA, Geha R, Elmarsafy AM
Clin Exp Immunol 2019 Feb;195(2):202-212. Epub 2018 Nov 4 doi: 10.1111/cei.13222. PMID: 30307608Free PMC Article
Late Onset Hypomorphic RAG2 Deficiency Presentation with Fatal Vaccine-Strain VZV Infection.
Dutmer CM, Asturias EJ, Smith C, Dishop MK, Schmid DS, Bellini WJ, Tirosh I, Lee YN, Notarangelo LD, Gelfand EW
J Clin Immunol 2015 Nov;35(8):754-60. Epub 2015 Oct 29 doi: 10.1007/s10875-015-0207-8. PMID: 26515615Free 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
Hypomorphic RAG deficiency: impact of disease burden on survival and thymic recovery argues for early diagnosis and HSCT.
Schuetz C, Gerke J, Ege M, Walter J, Kusters M, Worth A, Kanakry JA, Dimitrova D, Wolska-Kuśnierz B, Chen K, Unal E, Karakukcu M, Pashchenko O, Leiding J, Kawai T, Amrolia PJ, Berghuis D, Buechner J, Buchbinder D, Cowan MJ, Gennery AR, Güngör T, Heimall J, Miano M, Meyts I, Morris EC, Rivière J, Sharapova SO, Shaw PJ, Slatter M, Honig M, Veys P, Fischer A, Cavazzana M, Moshous D, Schulz A, Albert MH, Puck JM, Lankester AC, Notarangelo LD, Neven B
Blood 2023 Feb 16;141(7):713-724. doi: 10.1182/blood.2022017667. PMID: 36279417Free PMC Article
Unrelated Hematopoietic Cell Transplantation in a Patient with Combined Immunodeficiency with Granulomatous Disease and Autoimmunity Secondary to RAG Deficiency.
John T, Walter JE, Schuetz C, Chen K, Abraham RS, Bonfim C, Boyce TG, Joshi AY, Kang E, Carvalho BT, Mahajerin A, Nugent D, Puthenveetil G, Soni A, Su H, Cowan MJ, Notarangelo L, Buchbinder D
J Clin Immunol 2016 Oct;36(7):725-32. Epub 2016 Aug 18 doi: 10.1007/s10875-016-0326-x. PMID: 27539235Free PMC Article
Late Onset Hypomorphic RAG2 Deficiency Presentation with Fatal Vaccine-Strain VZV Infection.
Dutmer CM, Asturias EJ, Smith C, Dishop MK, Schmid DS, Bellini WJ, Tirosh I, Lee YN, Notarangelo LD, Gelfand EW
J Clin Immunol 2015 Nov;35(8):754-60. Epub 2015 Oct 29 doi: 10.1007/s10875-015-0207-8. PMID: 26515615Free PMC Article
Identification of severe combined immunodeficiency by T-cell receptor excision circles quantification using neonatal guthrie cards.
Morinishi Y, Imai K, Nakagawa N, Sato H, Horiuchi K, Ohtsuka Y, Kaneda Y, Taga T, Hisakawa H, Miyaji R, Endo M, Oh-Ishi T, Kamachi Y, Akahane K, Kobayashi C, Tsuchida M, Morio T, Sasahara Y, Kumaki S, Ishigaki K, Yoshida M, Urabe T, Kobayashi N, Okimoto Y, Reichenbach J, Hashii Y, Tsuji Y, Kogawa K, Yamaguchi S, Kanegane H, Miyawaki T, Yamada M, Ariga T, Nonoyama S
J Pediatr 2009 Dec;155(6):829-33. Epub 2009 Jul 22 doi: 10.1016/j.jpeds.2009.05.026. PMID: 19628217

Prognosis

Hypomorphic RAG deficiency: impact of disease burden on survival and thymic recovery argues for early diagnosis and HSCT.
Schuetz C, Gerke J, Ege M, Walter J, Kusters M, Worth A, Kanakry JA, Dimitrova D, Wolska-Kuśnierz B, Chen K, Unal E, Karakukcu M, Pashchenko O, Leiding J, Kawai T, Amrolia PJ, Berghuis D, Buechner J, Buchbinder D, Cowan MJ, Gennery AR, Güngör T, Heimall J, Miano M, Meyts I, Morris EC, Rivière J, Sharapova SO, Shaw PJ, Slatter M, Honig M, Veys P, Fischer A, Cavazzana M, Moshous D, Schulz A, Albert MH, Puck JM, Lankester AC, Notarangelo LD, Neven B
Blood 2023 Feb 16;141(7):713-724. doi: 10.1182/blood.2022017667. PMID: 36279417Free PMC Article
RAG1 splicing mutation causes enhanced B cell differentiation and autoantibody production.
Min Q, Meng X, Zhou Q, Wang Y, Li Y, Lai N, Xiong E, Wang W, Yasuda S, Yu M, Zhang H, Sun J, Wang X, Wang JY
JCI Insight 2021 Oct 8;6(19) doi: 10.1172/jci.insight.148887. PMID: 34622798Free PMC Article
Identification of severe combined immunodeficiency by T-cell receptor excision circles quantification using neonatal guthrie cards.
Morinishi Y, Imai K, Nakagawa N, Sato H, Horiuchi K, Ohtsuka Y, Kaneda Y, Taga T, Hisakawa H, Miyaji R, Endo M, Oh-Ishi T, Kamachi Y, Akahane K, Kobayashi C, Tsuchida M, Morio T, Sasahara Y, Kumaki S, Ishigaki K, Yoshida M, Urabe T, Kobayashi N, Okimoto Y, Reichenbach J, Hashii Y, Tsuji Y, Kogawa K, Yamaguchi S, Kanegane H, Miyawaki T, Yamada M, Ariga T, Nonoyama S
J Pediatr 2009 Dec;155(6):829-33. Epub 2009 Jul 22 doi: 10.1016/j.jpeds.2009.05.026. PMID: 19628217

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: 37567393
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
Hypomorphic RAG deficiency: impact of disease burden on survival and thymic recovery argues for early diagnosis and HSCT.
Schuetz C, Gerke J, Ege M, Walter J, Kusters M, Worth A, Kanakry JA, Dimitrova D, Wolska-Kuśnierz B, Chen K, Unal E, Karakukcu M, Pashchenko O, Leiding J, Kawai T, Amrolia PJ, Berghuis D, Buechner J, Buchbinder D, Cowan MJ, Gennery AR, Güngör T, Heimall J, Miano M, Meyts I, Morris EC, Rivière J, Sharapova SO, Shaw PJ, Slatter M, Honig M, Veys P, Fischer A, Cavazzana M, Moshous D, Schulz A, Albert MH, Puck JM, Lankester AC, Notarangelo LD, Neven B
Blood 2023 Feb 16;141(7):713-724. doi: 10.1182/blood.2022017667. PMID: 36279417Free PMC Article
Clinical Manifestations, Mutational Analysis, and Immunological Phenotype in Patients with RAG1/2 Mutations: First Cases Series from Mexico and Description of Two Novel Mutations.
Lugo-Reyes SO, Pastor N, González-Serrano E, Yamazaki-Nakashimada MA, Scheffler-Mendoza S, Berron-Ruiz L, Wakida G, Nuñez-Nuñez ME, Macias-Robles AP, Staines-Boone AT, Venegas-Montoya E, Alaez-Verson C, Molina-Garay C, Flores-Lagunes LL, Carrillo-Sanchez K, Niemela J, Rosenzweig SD, Gaytan P, Yañez JA, Martinez-Duncker I, Notarangelo LD, Espinosa-Padilla S, Cruz-Munoz ME
J Clin Immunol 2021 Aug;41(6):1291-1302. Epub 2021 May 5 doi: 10.1007/s10875-021-01052-0. PMID: 33954879Free PMC Article
Identification of severe combined immunodeficiency by T-cell receptor excision circles quantification using neonatal guthrie cards.
Morinishi Y, Imai K, Nakagawa N, Sato H, Horiuchi K, Ohtsuka Y, Kaneda Y, Taga T, Hisakawa H, Miyaji R, Endo M, Oh-Ishi T, Kamachi Y, Akahane K, Kobayashi C, Tsuchida M, Morio T, Sasahara Y, Kumaki S, Ishigaki K, Yoshida M, Urabe T, Kobayashi N, Okimoto Y, Reichenbach J, Hashii Y, Tsuji Y, Kogawa K, Yamaguchi S, Kanegane H, Miyawaki T, Yamada M, Ariga T, Nonoyama S
J Pediatr 2009 Dec;155(6):829-33. Epub 2009 Jul 22 doi: 10.1016/j.jpeds.2009.05.026. PMID: 19628217

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