A novel homozygous RAG1 mutation is associated with severe combined immunodeficiency and neurological presentations
Main Article Content
Keywords
severe combined immunodeficiency, SCID, recombination activating gene, RAG1, targeted sequencing, NGS
Abstract
Introduction and objectives: Severe combined immunodeficiency (SCID) is a subset of primary immunodeficiency diseases caused by a hereditary deficiency of the adaptive immune system. Mutation in recombination activating gene (RAG) is known as the underlying genetic cause of SCID. RAG protein plays a pivotal role in V(D)J recombination which is the main process to assemble lymphocyte antigen receptors during T- and B-cell development. The patients are characterized by recurrent infections, failure to thrive, chronic diarrhea, and fever, in early infancy. Herein, we present a case of SCID with rare neurological manifestations affected by a mutation in RAG1.
Patients and methods: The patient was a 15-month-old infant born to a consanguineous family. She was presented with neurological abnormalities including facial nerve palsy, seizure, and decreased consciousness. Next-generation sequencing (NGS)-based primary immunodeficiency disease (PID)-gene panel screen and Sanger sequencing were performed to identify the genetic mutation.
Results: We found a novel homozygous missense mutation in RAG1, c.1210C>T,p.Arg404Trp, which was predicted to be deleterious (combined annotation dependent depletion, CADD score of 27.4). Both parents were heterozygous carriers for this mutation. According to her laboratory data, both T cell and B cell numbers were decreased and the patient was diagnosed as RAG1- SCID.
Conclusions: SCID is a pediatric emergency with a variety of manifestations in infants. Therefore, accurate diagnosis importantly in the case of rare manifestations must be considered in these patients. Our findings point toward the importance of genetic assessment for early diagnosis and timely treatment of this disorder.
References
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22. Villa A, Notarangelo LD, Roifman CM. Omenn syndrome: inflammation in leaky severe combined immunodeficiency. J Allergy Clin. Immunol. 2008;122(6):1082–1086. 10.1016/j.jaci.2008.09.037
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24. Villa A, Sobacchi C, Notarangelo LD, Bozzi F, Abinun M, Abrahamsen TG, et al. V (D) J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations. Blood. 2001;97(1):81–88. 10.1182/blood.V97.1.81
25. de Villartay J-P, Lim A, Al-Mousa H, Dupont S, Déchanet-Merville J, Coumau-Gatbois E, et al. A novel immunodeficiency associated with hypomorphic RAG1 mutations and CMV infection. J Clin Invest. 2005;115(11):3291–3299. 10.1172/JCI25178
26. Ehl S, Schwarz K, Enders A, Duffner U, Pannicke U, Kühr J, et al. A variant of SCID with specific immune responses and predominance of γδ T cells. J Clin Invest. 2005;115(11):3140–3148. 10.1172/JCI25221
27. Karaca NE, Aksu G, Genel F, Gulez N, Can S, Aydinok Y, et al. Diverse phenotypic and genotypic presentation of RAG1 mutations in two cases with SCID. Clin Exp Med. 2009;9(4):339. 10.1007/s10238-009-0053-1
28. Carmona LM, Schatz DG. New insights into the evolutionary origins of the recombination-activating gene proteins and V (D) J recombination. FEBS J. 2017;284(11):1590–1605. 10.1111/febs.13990
29. Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nature Genet. 2014;46(3):310–315. 10.1038/ng.2892
30. Corneo B, Moshous D, Gungor T, Wulffraat N, Philippet P, et al. Identical mutations in RAG1 or RAG2 genes leading to defective V(D)J recombinase activity can cause either T-B–severe combined immune deficiency or Omenn syndrome. Blood. 2001;97:2772-2776. 10.1182/blood.V97.9.2772
31. Dhingra N, Yadav SP, de Villartay J-P, Picard C, Sabharwal R, Dinand V, et al. Severe combined immunodeficiency caused by a new homozygous RAG1 mutation with progressive encephalopathy. Hematol Oncol Stem Cell Ther. 2014;7(1):44–49. 10.1016/j.hemonc.2013.11.001
32. Aydin ÖF, Anlar B. Neurological manifestations of primary immunodeficiency diseases. Clin Pediatr. 2018;57(7):761–774. 10.1177/0009922817737083
33. Dehkordy SF, Aghamohammadi A, Ochs HD, Rezaei N. Primary immunodeficiency diseases associated with neurologic manifestations. J Clin Immunol. 2012;32(1):1–24. 10.1007/s10875-011-9593-8
34. Nofech-Mozes Y, Roifman C. Neurological manifestations in severe combined immunodeficiency secondary to adenosine deaminase deficiency: three case reports and review of the literature. J Allergy Clin Immunol. 2005;115(2):S78. 10.1016/j.jaci.2004.12.325
35. Enders A, Fisch P, Schwarz K, Duffner U, Pannicke U, Nikolopoulos E, et al. A severe form of human combined immunodeficiency due to mutations in DNA ligase IV. J Immunol. 2006;176(8):5060–5068. 10.4049/jimmunol.176.8.5060
36. Frippiat C, Kremarik P, Ropars A, Dournon C, Frippiat J-P. The recombination-activating gene 1 of Pleurodeles waltl (urodele amphibian) is transcribed in lymphoid tissues and in the central nervous system. Immunogenetics. 2001;52(3–4):264–275. 10.1007/s002510000275
37. Mombaerts P, Iacomini J, Johnson RS, Herrup K, Tonegawa S, Papaioannou VE. RAG-1-deficient mice have no mature B and T lymphocytes. Cell. 1992;68(5):869–877. 10.1016/0092-8674(92)90030-G
38. Milner JD, Fasth A, Etzioni A. Autoimmunity in severe combined immunodeficiency (SCID): lessons from patients and experimental models. J Clin Immunol. 2008;28(1):29. 10.1007/s10875-007-9159-y
39. Waruiru C, Slatter MA, Taylor C, Ramesh V, Flood TJ, Abinun M, et al. Outcome of hematopoietic stem cell transplantation in severe combined immune deficiency with central nervous system viral infection. Pediatr Infect Dis J. 2007;26(2):129–133. 10.1097/01.inf.0000250621.46742.b5
40. Buckley RH. Transplantation of hematopoietic stem cells in human severe combined immunodeficiency: longterm outcomes. Immunol Res. 2011;49(1–3):25–43. 10.1007/s12026-010-8191-9
41. Castagnoli R, Delmonte OM, Calzoni E, Notarangelo LD. Hematopoietic stem cell transplantation in primary immunodeficiency diseases: current status and future perspectives. Front Pediatr. 2019;7:295. 10.3389/fped.2019.00295
42. Vertès AA. The potential of cytotherapeutics in hematologic reconstitution and in the treatment and prophylaxis of graft-versus-host disease. Chapter I: current practice and remaining unmet medical needs. Regen Med. 2015;10(3):331–343. 10.2217/rme.15.12
43. Cavazzana-Calvo M, Fischer A. Gene therapy for severe combined immunodeficiency: Are we there yet? J Clin Invest. 2007;117(6):1456–1465. 10.1172/JCI30953
44. Gaspar HB, Thrasher AJ. Gene therapy for severe combined immunodeficiencies. Expert Opin Biol Ther. 2005;5(9):1175–1182. 10.1517/14712598.5.9.1175
45. Aiuti A. Advances in gene therapy for ADA-deficient SCID. Curr Opin Mol Ther. 2002;4(5):515–522. PMid: 12435054
46. Aiuti A, Cassani B, Andolfi G, Mirolo M, Biasco L, Recchia A, et al. Multilineage hematopoietic reconstitution without clonal selection in ADA-SCID patients treated with stem cell gene therapy. J Clin Invest. 2007;117(8):2233–2240. 10.1172/JCI31666
47. Aiuti A, Cattaneo F, Galimberti S, Benninghoff U, Cassani B, Callegaro L, et al. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. NEJM. 2009;360(5):447–458. 10.1056/NEJMoa0805817
48. Carlucci F, Tabucchi A, Aiuti A, Rosi F, Floccari F, Pagani R, et al. Evaluation of ADA gene expression and transduction efficiency in ADA/SCID patients undergoing gene therapy. Nucleosides Nucleotides Nucleic Acids. 2004;23(8–9):1245–1248. 10.1081/NCN-200027508
49. Garcia-Perez L, van Eggermond M, van Roon L, Vloemans S, Cordes M, Schambach A, et al. Successful preclinical development of gene therapy for recombinase activating gene-1-deficient SCID. Mol Ther Methods Clin Dev. 2020;17:666–682. 10.1016/j.omtm.2020.03.016
50. Van Til NP, Sarwari R, Visser TP, Hauer J, Lagresle-Peyrou C, Van Der Velden G, et al. Recombination-activating gene 1 (Rag1)-deficient mice with severe combined immunodeficiency treated with lentiviral gene therapy demonstrate autoimmune Omenn-like syndrome. J Allergy Clin Immunol. 2014;133(4):1116–1123. 10.1016/j.jaci.2013.10.009
2. Cossu F. Genetics of SCID. Ital J Pediatr. 2010;36(1):76. 10.1186/1824-7288-36-76
3. Pourvali A, Arshi S, Nabavi M, Bemanian MH, Shokri S, Shahrooei M, et al. Atypical Omenn syndrome due to RAG2 gene mutation: a case report. Iran J Immunol. 2019;16(4):334–338. 10.22034/IJI.2019.80285
4. Picard C, Al-Herz W, Bousfiha A, Casanova J-L, Chatila T, Conley ME, et al. Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015. J Clin Immunol. 2015;35(8):696–726. 10.1007/s10875-015-0201-1
5. Ogando JCB, Gaytán AP, Becerra JCA, Cardona AÁ, Bezrodnik L, Borzutzky A, et al. Latin American consensus on the supportive management of patients with severe combined immunodeficiency. J Allergy Clin Immunol. 2019;144(4):897–905. 10.1016/j.jaci.2019.08.002
6. Woodbine L, Neal JA, Sasi N-K, Shimada M, Deem K, Coleman H, et al. PRKDC mutations in a SCID patient with profound neurological abnormalities. J Clin Invest. 2013;123(7):2969–2980. 10.1172/JCI67349
7. Gennery A, Cant A. Diagnosis of severe combined immunodeficiency. J Clin Pathol. 2001;54(3):191–195. 10.1136/jcp.54.3.191
8. Puck JM, Pepper AE, Henthorn PS, Candotti F, Isakov J, Whitwam T, et al. Mutation analysis of IL2RG in human X-linked severe combined immunodeficiency. Blood. 1997;89(6):1968–1977. PMid: 9058718
9. Kalman L, Lindegren ML, Kobrynski L, Vogt R, Hannon H, Howard JT, et al. Mutations in genes required for T-cell development: IL7R, CD45, IL2RG, JAK3, RAG1, RAG2, ARTEMIS, and ADA and severe combined immunodeficiency: HuGE review. Genet Med. 2004;6(1):16–26. 10.1097/01.GIM.0000105752.80592.A3
10. Tangye SG, Al-Herz W, Bousfiha A, Chatila T, Cunningham-Rundles C, Etzioni A, et al. Human inborn errors of immunity: 2019 update on the classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2020;40(1):24–64. 10.1007/s10875-020-00763-0
11. Shahbazi Z, Yazdani R, Shahkarami S, Shahbazi S, Hamid M, Sadeghi-Shabestari M, et al. Genetic mutations and immunological features of severe combined immunodeficiency patients in Iran. Immunol Lett. 2019;216:70–78. 10.1016/j.imlet.2019.10.001
12. Parvaneh N, Casanova J-L, Notarangelo LD, Conley ME. Primary immunodeficiencies: a rapidly evolving story. J Allergy Clin Immunol. 2013;131(2):314–323. 10.1016/j.jaci.2012.11.051
13. Safaei S, Pourpak Z, Moin M, Houshmand M. IL7R and RAG1/2 genes mutations/polymorphisms in patients SCID. Iran J Allergy Asthma Immunol. 2011;10(2):129–132. PMid: 21625022
14. Hesslein DG, Schatz DG. Factors and forces controlling V (D) J recombination. Adv Immunol. 2001;78:169–232. 10.1016/S0065-2776(01)78004-2
15. Gellert M. V (D) J recombination: RAG proteins, repair factors, and regulation. Annu Rev Biochem. 2002;71(1):101–132. 10.1146/annurev.biochem.71.090501.150203
16. Buckley RH, Schiff RI, Schiff SE, Markert ML, Williams LW, Harville TO, et al. Human severe combined immunodeficiency: genetic, phenotypic, and functional diversity in one hundred eight infants. J Pediatr. 1997;130(3):378–387. 10.1016/S0022-3476(97)70199-9
17. van Der Burg M, Weemaes C, Preijers F, Brons P, Barendregt BH, van Tol M, et al. B-cell recovery after stem cell transplantation of Artemis-deficient SCID requires elimination of autologous bone marrow precursor-B-cells. Haematologica. 2006;91(12):1705–1709. PMid: 17145611
18. Sobacchi C, Marrella V, Rucci F, Vezzoni P, Villa A. RAG-dependent primary immunodeficiencies. Human Mutation. 2006;27(12):1174–1184. 10.1002/humu.20408
19. Asai E, Wada T, Sakakibara Y, Toga A, Toma T, Shimizu T, et al. Analysis of mutations and recombination activity in RAG-deficient patients. Clin Immunol. 2011;138(2):172–177. 10.1016/j.clim.2010.11.005
20. Barthels C, Puchałka J, Racek T, Klein C, Brocker T. Novel spontaneous deletion of Artemis exons 10 and 11 in mice leads to T-and B-cell deficiency. PLoS One. 2013;8(9):e74838. 10.1371/journal.pone.0074838
21. Hönig M, Schwarz K. Omenn syndrome: a lack of tolerance on the background of deficient lymphocyte development and maturation. Curr Opin Rheumatol. 2006;18(4):383–388. 10.1097/01.bor.0000231907.50290.6f
22. Villa A, Notarangelo LD, Roifman CM. Omenn syndrome: inflammation in leaky severe combined immunodeficiency. J Allergy Clin. Immunol. 2008;122(6):1082–1086. 10.1016/j.jaci.2008.09.037
23. Santagata S, Villa A, Sobacchi C, Cortes P, Vezzoni P. The genetic and biochemical basis of Omenn syndrome. Immunol Rev. 2000;178:64–74. 10.1034/j.1600-065X.2000.17818.x
24. Villa A, Sobacchi C, Notarangelo LD, Bozzi F, Abinun M, Abrahamsen TG, et al. V (D) J recombination defects in lymphocytes due to RAG mutations: severe immunodeficiency with a spectrum of clinical presentations. Blood. 2001;97(1):81–88. 10.1182/blood.V97.1.81
25. de Villartay J-P, Lim A, Al-Mousa H, Dupont S, Déchanet-Merville J, Coumau-Gatbois E, et al. A novel immunodeficiency associated with hypomorphic RAG1 mutations and CMV infection. J Clin Invest. 2005;115(11):3291–3299. 10.1172/JCI25178
26. Ehl S, Schwarz K, Enders A, Duffner U, Pannicke U, Kühr J, et al. A variant of SCID with specific immune responses and predominance of γδ T cells. J Clin Invest. 2005;115(11):3140–3148. 10.1172/JCI25221
27. Karaca NE, Aksu G, Genel F, Gulez N, Can S, Aydinok Y, et al. Diverse phenotypic and genotypic presentation of RAG1 mutations in two cases with SCID. Clin Exp Med. 2009;9(4):339. 10.1007/s10238-009-0053-1
28. Carmona LM, Schatz DG. New insights into the evolutionary origins of the recombination-activating gene proteins and V (D) J recombination. FEBS J. 2017;284(11):1590–1605. 10.1111/febs.13990
29. Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nature Genet. 2014;46(3):310–315. 10.1038/ng.2892
30. Corneo B, Moshous D, Gungor T, Wulffraat N, Philippet P, et al. Identical mutations in RAG1 or RAG2 genes leading to defective V(D)J recombinase activity can cause either T-B–severe combined immune deficiency or Omenn syndrome. Blood. 2001;97:2772-2776. 10.1182/blood.V97.9.2772
31. Dhingra N, Yadav SP, de Villartay J-P, Picard C, Sabharwal R, Dinand V, et al. Severe combined immunodeficiency caused by a new homozygous RAG1 mutation with progressive encephalopathy. Hematol Oncol Stem Cell Ther. 2014;7(1):44–49. 10.1016/j.hemonc.2013.11.001
32. Aydin ÖF, Anlar B. Neurological manifestations of primary immunodeficiency diseases. Clin Pediatr. 2018;57(7):761–774. 10.1177/0009922817737083
33. Dehkordy SF, Aghamohammadi A, Ochs HD, Rezaei N. Primary immunodeficiency diseases associated with neurologic manifestations. J Clin Immunol. 2012;32(1):1–24. 10.1007/s10875-011-9593-8
34. Nofech-Mozes Y, Roifman C. Neurological manifestations in severe combined immunodeficiency secondary to adenosine deaminase deficiency: three case reports and review of the literature. J Allergy Clin Immunol. 2005;115(2):S78. 10.1016/j.jaci.2004.12.325
35. Enders A, Fisch P, Schwarz K, Duffner U, Pannicke U, Nikolopoulos E, et al. A severe form of human combined immunodeficiency due to mutations in DNA ligase IV. J Immunol. 2006;176(8):5060–5068. 10.4049/jimmunol.176.8.5060
36. Frippiat C, Kremarik P, Ropars A, Dournon C, Frippiat J-P. The recombination-activating gene 1 of Pleurodeles waltl (urodele amphibian) is transcribed in lymphoid tissues and in the central nervous system. Immunogenetics. 2001;52(3–4):264–275. 10.1007/s002510000275
37. Mombaerts P, Iacomini J, Johnson RS, Herrup K, Tonegawa S, Papaioannou VE. RAG-1-deficient mice have no mature B and T lymphocytes. Cell. 1992;68(5):869–877. 10.1016/0092-8674(92)90030-G
38. Milner JD, Fasth A, Etzioni A. Autoimmunity in severe combined immunodeficiency (SCID): lessons from patients and experimental models. J Clin Immunol. 2008;28(1):29. 10.1007/s10875-007-9159-y
39. Waruiru C, Slatter MA, Taylor C, Ramesh V, Flood TJ, Abinun M, et al. Outcome of hematopoietic stem cell transplantation in severe combined immune deficiency with central nervous system viral infection. Pediatr Infect Dis J. 2007;26(2):129–133. 10.1097/01.inf.0000250621.46742.b5
40. Buckley RH. Transplantation of hematopoietic stem cells in human severe combined immunodeficiency: longterm outcomes. Immunol Res. 2011;49(1–3):25–43. 10.1007/s12026-010-8191-9
41. Castagnoli R, Delmonte OM, Calzoni E, Notarangelo LD. Hematopoietic stem cell transplantation in primary immunodeficiency diseases: current status and future perspectives. Front Pediatr. 2019;7:295. 10.3389/fped.2019.00295
42. Vertès AA. The potential of cytotherapeutics in hematologic reconstitution and in the treatment and prophylaxis of graft-versus-host disease. Chapter I: current practice and remaining unmet medical needs. Regen Med. 2015;10(3):331–343. 10.2217/rme.15.12
43. Cavazzana-Calvo M, Fischer A. Gene therapy for severe combined immunodeficiency: Are we there yet? J Clin Invest. 2007;117(6):1456–1465. 10.1172/JCI30953
44. Gaspar HB, Thrasher AJ. Gene therapy for severe combined immunodeficiencies. Expert Opin Biol Ther. 2005;5(9):1175–1182. 10.1517/14712598.5.9.1175
45. Aiuti A. Advances in gene therapy for ADA-deficient SCID. Curr Opin Mol Ther. 2002;4(5):515–522. PMid: 12435054
46. Aiuti A, Cassani B, Andolfi G, Mirolo M, Biasco L, Recchia A, et al. Multilineage hematopoietic reconstitution without clonal selection in ADA-SCID patients treated with stem cell gene therapy. J Clin Invest. 2007;117(8):2233–2240. 10.1172/JCI31666
47. Aiuti A, Cattaneo F, Galimberti S, Benninghoff U, Cassani B, Callegaro L, et al. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. NEJM. 2009;360(5):447–458. 10.1056/NEJMoa0805817
48. Carlucci F, Tabucchi A, Aiuti A, Rosi F, Floccari F, Pagani R, et al. Evaluation of ADA gene expression and transduction efficiency in ADA/SCID patients undergoing gene therapy. Nucleosides Nucleotides Nucleic Acids. 2004;23(8–9):1245–1248. 10.1081/NCN-200027508
49. Garcia-Perez L, van Eggermond M, van Roon L, Vloemans S, Cordes M, Schambach A, et al. Successful preclinical development of gene therapy for recombinase activating gene-1-deficient SCID. Mol Ther Methods Clin Dev. 2020;17:666–682. 10.1016/j.omtm.2020.03.016
50. Van Til NP, Sarwari R, Visser TP, Hauer J, Lagresle-Peyrou C, Van Der Velden G, et al. Recombination-activating gene 1 (Rag1)-deficient mice with severe combined immunodeficiency treated with lentiviral gene therapy demonstrate autoimmune Omenn-like syndrome. J Allergy Clin Immunol. 2014;133(4):1116–1123. 10.1016/j.jaci.2013.10.009
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Melika, S., Hossein, E., Mona, S., Elham, R., Samaneh, Z., Sepideh, S., Raul Jimenez, H., Ana, K., Kaan, B., & Nima, R. (2021). A novel homozygous RAG1 mutation is associated with severe combined immunodeficiency and neurological presentations. Allergologia Et Immunopathologia, 49(4), 91-97. https://doi.org/10.15586/aei.v49i4.194
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How to Cite
Melika, S., Hossein, E., Mona, S., Elham, R., Samaneh, Z., Sepideh, S., Raul Jimenez, H., Ana, K., Kaan, B., & Nima, R. (2021). A novel homozygous RAG1 mutation is associated with severe combined immunodeficiency and neurological presentations. Allergologia Et Immunopathologia, 49(4), 91-97. https://doi.org/10.15586/aei.v49i4.194