Abnormalities in the number and structure of chromosomes, associated with immunodeficiencies

Yarema N., Boyarchuk O., Chornomydz I., Panasiuk Y.

Review 

SUMMARY. Recurrent infections in children with chromosomal abnormalities are associated with anatomical features of the upper respiratory tract and neuromuscular disorders, however, immunological abnormalities may increase susceptibility to infections. The article analyses the studies of the immune system of children with chromosomal abnormalities. The search in the international databases OMIM, Scopus, and PubMed was conducted using the keywords. The immunological examination of children with Down syndrome, 22q11.2 deletion, Nijme-gen, Louis-Bar, Turner, Wolf-Hirschhorn, Jacobsen, CHARGE, Cornelia de Lange demonstrated their immunodeficiency, manifested in the changes in cellular immunity and hypogammaglobulinemia. The article highlights the pathogenetic mechanisms of immunological deviations in children with chromosomal abnormalities. It is emphasized that during the neonatal screening for severe combined immunodeficiency, T-cell lymphopenia is detected in patients with chromosomal abnormalities, so they should be considered a group with a high risk of immunodeficiency. Early diagnosis of chromosomal diseases will determine the severity of immunological disorders, enable their timely correction, prevent infectious complications, and improve life quality.

Key words: chromosome anomalies, immunodeficiency recurrent infections, neonatal screening

Tsitologiya i Genetika 2021, vol. 55, no. 4, pp. 54-64

• Ternopil National Medical University of the Ministry of Health of Ukraine, Ternopil, Ukraine, 1, Maydan Voli, Ternopil, 46001, Ukraine

E-mail: yarema_nm tdmu.edu.ua, boyarchuk tdmu.edu.ua, shornomudz_ib tdmu.edu.ua, panasiuk tdmu.edu.ua

Yarema N., Boyarchuk O., Chornomydz I., Panasiuk Y. Abnormalities in the number and structure of chromosomes, associated with immunodeficiencies, Tsitol Genet., 2021, vol. 55, no. 4, pp. 54-64.

In "Cytology and Genetics":
N. M. Yarema, O. R. Boyarchuk, I. B. Chornomydz & Ya. V. Panasiuk Numerical and Structural Chromosomal Abnormalities Associated with Immunodeficiency, Cytol Genet., 2021, vol. 55, no. 4, pp. 340–349
DOI: 10.3103/S0095452721040137

References

1. Aghamohammad, A., Moin, M., Kouhi, A., Mohagheghi, M.-A., Shirazi, A., Rezaei, N., and Ghaffari, S.R., Chromosomal radiosensitivity in patients with common variable immunodeficiency, Immunobiology, 2008, vol. 213, no. 5, pp. 447–454. https://doi.org/10.1016/j.imbio.2007.10.018

2. Antonarakis, S.E., Skotko, B.G., Rafii, M.S., et al., Down syndrome, Nat. Rev. Dis. Primers, 2020, vol. 6, no. 1, pp. 1–20.

3. Baker, M.W., Grossman, W.J., Laessig, R.H., et al., Development of a routine newborn screening protocol for severe combined immunodeficiency, J. Allerg. Clin. Immunol., 2009, vol. 124, pp. 522–527.https://doi.org/10.1016/j.jaci.2009.04.007

4. Barmettler, S., Coffey, K., Smith, M.J., Chong, H.J., Pozos, T.C., Seroogy, C.M., and Abraham, R.S., Functional confirmation of DNA repair defect in ataxia telangiectasia (AT) infants identified by newborn screening for severe combined immunodeficiency (NBS SCID), J. Allerg. Clin. Immun. In Practice, 2020. https://doi.org/10.1016/j.jaip.2020.08.008

5. Bjurkman, A.D., Van der Burg, Cormier-Daire, V., et al., Reduced immunoglobulin gene diversity in patients with Cornelia de Lange syndrome, J. Allerg. Clin. Immun., 2018, vol. 141, no. 1, pp. 408–411.e8. https://doi.org/10.1016/j.jaci.2017.06.043

6. Bloemers, B.L., Broers, C.J., Bont, L., et al., Increased risk of respiratory tract infections in children with Down syndrome: the consequence of an altered immune system, Microb. Infect., 2010, vol. 12, no. 11, pp. 799– 808. https://doi.org/10.1016/j.micinf.2010.05.007

7. Boyarchuk, O. and Dmytrash, L., Clinical manifestations in the patients with primary immunodeficiencies: data from one regional center, Turk. J. Immun., 2019, vol. l7, no. 3, pp. 113–119. https://doi.org/10.25002/tji.2019.1168

8. Boyarchuk, O., Volyanska, L., and Dmytrash, L., Clinical variability of chromosome 22q11.2 deletion syndrome, Centr. Eur. J. Immun., 2017, vol. 42, no. 4, pp. 412–417. https://doi.org/10.5114/ceji.2017.72818

9. Boyarchuk, O., Volyanska, L., Kosovska, T., Lewandowicz-Uszynska, A., and Kinash, M., Awareness about primary immunodeficiency diseases among medical students, Georg. Med. News, 2018, vol. 12, no. 285, pp. 124–130.

10. Boyarchuk, O., Balatska, N., and Chornomydz, I., Evaluation of warning signs of primary immunodeficiencies, Pediatria Polska (Pol. J. Paediatr.), 2019a, vol. 94, no. 6, pp. 337–341. https://doi.org/10.5114/polp.2019.92824

11. Boyarchuk, O., Kinash, M., Hariyan, T., and Bakalyuk, T., Evaluation of knowledge about primary immunodeficiencies among postgraduate medical students, Arch. Balkan Med. Union, 2019b, vol. 54, no. 1, pp. 11–19. https://doi.org/10.31688/ABMU.2019.54/1.18

12. Boyarchuk, O., Volokha, A., Hariyan, T., et al., The impact of combining educational program with the improving of infrastructure to diagnose on early detection of primary immunodeficiencies in children, Immunol. Res., 2019c, vol. 67, nos. 4–5, pp. 390–397. https://doi.org/10.1007/s12026-019-09103-w

13. Chi, X., Li, Y., and Qiu, X., V(D)J recombination, somatic hypermutation and class switch recombination of immunoglobulins: mechanism and regulation, Immunology, 2020. https://doi.org/10.1111/imm.13176

14. Choi, M. and Klingensmith, J., Chordin is a modifier of Tbx1 for the craniofacial malformations of 22q11 deletion syndrome phenotypes in mouse, PLos Genet., 2009, vol. 5, no. 2, pp. 1–8. https://doi.org/10.1371/journal.pgen.1000395

15. Cruz, N.V., Mahmoud, S.A., Chen, H., Lowery-Nordberg, M., Berlin, K., and Bahna, S.L., Follow-up study of immune defects in patients with dysmorphic disorders, Ann. Allergy, Asthma Immunol., 2009, vol. 102, no. 5, pp. 426–431. https://doi.org/10.1016/s1081-1206(10)60516-9

16. Cuadrado, E. and Barrena, M.J., Short analytical review: immune dysfunction in Down›s syndrome: primary immune deficiency or early senescence of the immune system, Clin. Immunol. Immunopathol., 1996, vol. 78, pp. 209–214. https://doi.org/10.1006/clin.1996.0031

17. Dai, Y., Kysela, B., Hanakahi, L.A., Manolis, K., Riballo, E., Stumm, M., and Jeggo, P.A., Nonhomologous end joining and V(D)J recombination require an additional factor, Proc. Natl. Acad. Sci. U. S. A., 2003, vol. 100, no. 5, pp. 2462– 2467. https://doi.org/10.1073/pnas.0437964100

18. Davey, B.T., Elder, R.W., Cloutier, M.M., Bennett, N., Lee, J.H., Wang, Z., and Toro-Salazar, O.H., T-cell receptor excision circles in newborns with congenital heart disease, J. Pediatr., 2019. https://doi.org/10.1016/j.jpeds.2019.05.061

19. De Villartay, J.P., Congenital defects in V(D)J recombination, Br. Med. Bull., 2015, vol. 114, no. 1.

20. Duarte, L., Ardison, M.J., Machado, R.A., et al., Rare case of Wolf–Hirschhorn involving the genes PIGG and PAOX, Braz. J. Surg. Clin. Res., 2020, vol. 30, no. 2), pp. 32–36.

21. Fechner, P.Y., Turner Syndrome, in Endocrine and Metabolic, Springer, 2020, pp. 157–174. https://doi.org/10.1007/978-3-030-34150-3

22. Fung, W.L., Butcher, N.J., Costain, G., et al., Practical guidelines for managing adults with 22q11.2 deletion syndrome, Genet. Med., 2015, vol. 17, no. 8, pp. 599–609. https://doi.org/10.1038/gim.2014.175

23. Gennery, A.R., Immunological aspects of 22q11.2 deletion syndrome, Cell Mol. Life Sci., 2011, vol. 69, no. 1, pp. 17–27. https://doi.org/10.1007/s00018-011-0842-z

24. Goldmuntz, E., 22q11.2 deletion syndrome and congenital heart disease, Am. J. Med. Genet. Part C: Semin. Med. Genet., 2020, vol. 184, no. 1, pp. 64–72. https://doi.org/10.1002/ajmg.c.31774

25. Grossfeld, P.D., Mattina, T., Lai, Z., et al., The 11q terminal deletion disorder: a prospective study of 110 cases, Am. J. Med. Genet. A, 2004, vol. 129, no. 1, pp. 51–61. https://doi.org/10.1002/ajmg.a.30090

26. Hammond, P., Hutton, T.J., Allanson, J.E., et al., Discriminating power of localized three-dimensional facial morphology, Am. J. Human Genet., 2005, vol. 77, no. 6, pp. 999–1010.https://doi.org/10.1086/498396

27. Hanley-Lopez, J., Estabrooks, L.L., and Stiehm, E.R., Antibody deficiencies in Wolf–Hirschhorn syndrome, J. Pediatr., 1998, vol. 133, pp. 141–143.https://doi.org/10.1016/s0022-3476(98)70194-5

28. Hariyan, T., Kinash, M., Kovalenko, R., and Boyarchuk, O., Evaluation of awareness about primary immunodeficiencies among physicians before and after implementation of the educational program: a longitudinal study, PLoS One, 2020, vol. 15, no. 5, e0233342.https://doi.org/10.1371/journal.pone.0233342

29. Hasbaoui, B.E., Elyajouri, A., Abilkassem, R., and Agadr, A., Nijmegen breakage syndrome: case report and review of literature, Pan. Afr. Med. J., 2020, vol. 35. https://doi.org/10.11604/pamj.2020.35.85.14746

30. Jyonouchi, S., Orange, J., Sullivan, et al., Immunologic features of Cornelia de Lange syndrome, Pediatrics, 2013, vol. 132, no. 2, pp. 484–489. https://doi.org/10.1542/peds.2012-3815

31. Karaman, S., Hazan, F., Erdem, S.B., Gelez, N., and Genel, F., Do microdeletions lead to immune deficiency?, Centr.-Eur. J. Immunol., 2020, vol. 45, no. 1, p. 69.https://doi.org/10.5114/ceji.2020.94671

32. Kerkel, K., Schupf, N., Hatta, K., et al., Altered DNA methylation in leukocytes with trisomy 21, PLoS Genet., 2010, vol. 6, no. 11, pp. 1–14. https://doi.org/10.1371/journal.pgen.1001212

33. Klein SL, Flanagan KL. (2016) Sex differences in immune responses. Nature Reviews Immunol 16(10): 626–638. https://doi.org/10.1038/nri.2016.90

34. Kobrynski LJ. (2019). Non-SCID T cell lymphopenia identified at Newborn Screening for Severe Combined Immune Deficiency. Annal Allerg, Asthma Immunol https://doi.org/10.1016/j.anai.2019.08.006

35. Kong Xiao-Fei, Worley, L., Rinchai, D., et al., Three copies of four interferon receptor genes underlie a mild type I interferonopathy in Down syndrome, J. Clin. Immunol., 2020, pp. 1–13. https://doi.org/10.1007/s10875-020-00803-9

36. Kozlova, O.I., Kostyuchenko, L.V., Polishchuk, R.S., et al., Non-Hodgkin’s lymphomas in children with chromosome instability syndromes, Oncology, 2011, vol. 13, no. 2, pp. 115–121.

37. Koonin, E.V. and Krupovic, M., Evolution of adaptive immunity from transposable elements combined with innate immune systems, Nat. Rev. Genet., 2015, vol. 3, pp. 184–192. https://dx.doi.org/10.1038%2Fnrg3859 https://doi.org/10.1038/nrg3859

38. Kruszka, P., Addissie, Y.A., Tekendo-Ngongang, C., et al., Turner syndrome in diverse populations, Am. J. Med. Genet. A, 2019, vol. 182, no. 2, pp. 303–313. https://doi.org/10.1002/ajmg.a.61461

39. Kusters, M.A., Verstegen, R.H., Gemen, E.F., and de Vries, E., Intrinsic defect of the immune system in children with Down syndrome: a review, Clin. Exp. Immunol., 2009, vol. 156, no. 2, pp. 189–193. https://doi.org/10.1111/j.1365-2249.2009.03890.x

40. Kutlug, S., Alpaslan, M.K., Hancioglu, G., Ozkan, S.E.O., Yesilirmak, D.C., Bulut, H., and Yildiran, A., Multiplex PCR-based newborn screening for severe T and B-cell lymphopenia: the first pilot study in Turkey, Med. Bull. Sisli Etfal Hospital, 2021.

41. Kwan, A., Abraham, R.S., Currier, R., et al., Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States, JAMA, 2014, vol. 312, no. 7, p. 729. https://doi.org/10.1001/jama.2014.9132

42. Lavin, M.F. and Yeo, A.J., Clinical potential of ATM inhibitors, in Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis, 2020, p. 111695. doi 10.1016/j.mrfmmm.2020.111695

43. Lichtner, P., Konig, R., Hasegawa, T., Van Esch, H., Meitinger, T., and Schuffenhauer, S., An HDR (hypo-parathyroidism, deafness, renal dysplasia) syndrome locus maps distal to the DiGeorge syndrome region on 10p13/14, J. Med. Genet., 2000, vol. 37, no. 1, pp. 33–37. https://doi.org/10.1136/jmg.37.1.33

44. Liu, C., Li, X., Cui, J., Dong, R., et al., Analysis of clinical and genetic characteristics in 10 Chinese individuals with Cornelia de Lange syndrome and literature review, Mol. Genet. Genom. Med., 2020. https://doi.org/10.1002/mgg3.1471

45. Lockstone, H.E., Harris, L.W., Swatton, J.E., Wayland, M.T., Holland, A.J., and Bahn, S., Gene expression profiling in the adult Down syndrome brain, Genomics, 2007, vol. 90, no. 6, pp. 647–660. https://doi.org/10.1016/j.ygeno.2007.08.005

46. Lorini, R., Ugazio, A.G., Cammareri, V., et al., Immunologic levels, T-cell markers, mitogen responsiveness and thymic hormone activity in Turner’s syndrome, Thymus, 1983, vol. 5, pp. 61–66.

47. Mahmoud, S.A., Lowery-Nordberg, M., Chen, H., Thurmon, T., Ursin, S., and Bahna, S.L., Immune defects in subjects with dysmorphic disorders, in Allergy and Asthma Proceedings, Ocean-Side Publications, 2005, vol. 26, no. 5, p. 373.

48. Marsh, R.A. and Lindsley, A.W., Genetic syndromes with associated immunodeficiencies, in Primary and Secondary Immunodeficiency: A Case-Based Guide to Evaluation and Management, 2021, p. 169.

49. Mauracher, A.A., Pagliarulo, F., Faes, L., et al., Causes of low neonatal T-cell receptor excision circles: a systematic review, J Allerg. Clin. Immun. In Practice, 2017, vol. 5, no. 5, pp. 1457–1460. e22. https://doi.org/10.1016/j.jaip.2017.02.009

50. McDonald-McGinn, D.M., Sullivan, K.E., Marino, B., et al., 22q11.2 deletion syndrome, Nat. Rev. Dis. Primers, 2015, vol. 1, no. 1, pp. 1–19. https://doi.org/10.1038/nrdp.2015.71

51. Ming, J.E. and Graham, J.M., Genetic syndromes with evidence of immune deficiency, in Stiehm’s Immune Deficiencies, 2014, pp. 281–324. https://doi.org/10.1016/b978-0-12-405546-9.00012-1

52. Ming, J.E. and Stiehm, E.R., Genetic syndromic immunodeficiencies with antibody defects, Immunol. Allerg. Clin. North Am., 2008, vol. 28, no. 4, pp. 715–736.

53. Ming, J.E., Stiehm, E.R., and Graham, J.M., Syndromic immunodeficiencies: genetic syndromes associated with immune abnormalities, Crit. Rev. Clin. Lab. Sci., 2003, vol. 40, no. 6, pp. 587–642. doi 10.1080/714037692

54. Ming, J.E., Stiehm, E.R., Ming, J.E., and Stiehm, E.R., Syndromic immunodeficiencies, in Primary Immunodeficiency Diseases, 2017, pp. 519–551. https://doi.org/10.1007/978-3-662-52909-6_10

55. Naspitz, C.K. and Sole, D., Selective deficiency of IgA: infrequent complications, Bol. Med. Hosp. Infant Mex., 1990, vol. 47, pp. 838–840.

56. Nussbaum, R.L., McInnes, R.R., Williard, H.F., Thompson, J.S., and Thompson, M.W., Genetics in Medicine, Philadelphia, PA: Saunders, 2007.

57. OMIM, Online Mendelian Inheritance in Man, OMIMt, Baltimore, MD: McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins Univ., 2013. http://omim.org/.

58. Packham, E.A. and Brook, J.D., T-box genes in human disorders, Hum. Mol. Genet., 2003, vol. 12, no. 1, pp. 37–44. https://doi.org/10.1093/hmg/ddg077

59. Patrawala, M. and Kobrynski, L., Nonsevere combined immunodeficiency T-cell lymphopenia identified through newborn screening, Curr. Opin. Allerg. Clin. Immun., 2019, vol. 19, no. 6, pp. 586–593.https://doi.org/10.1097/aci.0000000000000586

60. Picard, C., Al-Herz, W., Bousfiha, A., et al., Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency, J. Clin. Immunol., 2015, vol. 35, no. 8, pp. 696– 726. https://doi.org/10.1007/s10875-015-0201-1

61. Piliero, L.M., Sanford, A.N., McDonald-McGinn, D.M., Zackai, E.H., Sullivan, K.E., et al., T-cell homeostasis in humans with thymic hypoplasia due to chromosome 22q11.2 deletion syndrome, Blood, 2004, vol. 103, no. 3, pp. 1020–11025. https://doi.org/10.1093/hmg/ddg077

62. Proudhon, C., Hao, B., Raviram, R., Chaumeil, J., and Skok, J.A., Long-range regulation of V(D)J recombination. Molecular mechanisms that orchestrate the assembly of antigen receptor loci, 2015, pp. 123–182. https://doi.org/10.1016/bs.ai.2015.07.003

63. Puck, J.M., Neonatal screening for severe combined immunodeficiency, Curr. Opin. Pediatr., 2011, vol. 23, no. 6, pp. 667–673. https://doi.org/10.1097/mop.0b013e32834cb9b0

64. Rae, W., Indications to epigenetic dysfunction in the pathogenesis of common variable immunodeficiency, Arch. Immunol. Ther. Exp., 2016, vol. 65, no. 2, pp. 101–110. https://doi.org/10.1007/s00005-016-0414-x

65. Ram Chinen, J., Infections and immunodeficiency in Down syndrome, Clin. Exp. Immunol., 2011, vol. 164, no. 1, pp. 9–16.https://doi.org/10.1111/j.1365-2249.2011.04335.x

66. Roat, E., Prada, N., Lugli, E., et al., Homeostatic cytokines and expansion of regulatory T cells accompany thymic impairment in children with Down syndrome, Rejuvenation Res., 2008, vol. 11, no. 3, pp. 573–583. https://doi.org/10.1089/rej.2007.0648

67. Ru, H., Chambers, M.G., Fu, T.-M., Tong, A.B., Liao, M., and Wu, H., Molecular mechanism of V(D)J recombination from synaptic RAG1-RAG2 complex structures, Cell, 2015, vol. 163, no. 5, pp. 1138–1152. doi 10.1016/j.cell.2015.10.055

68. Ruud, H.J., Borte, S., Bok, L.A., et al., Impact of Down syndrome on the performance of neonatal screening assays for severe primary immunodeficiency diseases, J. Allerg. Clin. Immun., 2014, vol. 133, no. 4, pp. 1208–1211. https://doi.org/10.1016/j.jaci.2013.10.010

69. Sarogni, P., Pallotta, M.M., and Musio, A., Cornelia de Lange syndrome: from molecular diagnosis to therapeutic approach, J. Med. Genet., 2019. jmedgenet–2019–106277. https://doi.org/10.1136/jmedgenet-2019-106277

70. Schatorjé, E., van der Flier, M., Seppänen, M., Browning, M., Morsheimer, M., Henriet, S., and de Vries, E., Primary immunodeficiency associated with chromosomal aberration—an ESID survey, Orphanet. J. Rare Dis., 2016, vol. 11, no. 1. https://doi.org/10.1186/s13023-016-0492-1

71. Schatz, D.G. and Swanson, P.C., V(D)J recombination: mechanisms of initiation, Ann. Rev. Gene, 2011, vol. 45, no. 1, pp. 167–202. https://doi.org/10.1146/annurev-genet-110410-132552

72. Shcherbina, A. and Porras, O., DNA stability defects, in Stiehm’s Immune Deficiencies, 2020, pp. 281–318. doi 10.1016/b978-0-12-816768-7.00010-7

73. Stenberg, A.E, Sylvén, L., Magnusson, C.G., and Hultcrantz, M., Immunological parameters in girls with Turner syndrome, J. Negat. Res. BioMed., 2004, vol. 3, no. 1, pp. 268–272. https://doi.org/10.1186/1477-5751-3-6

74. Swillen, A. and McDonald-McGinn, D., Developmental trajectories in 22q11.2 deletion syndrome, Am. J. Med. Genet. C: Semin. Med. Genet., 2015, vol. 169, no. 2, pp. 172–181. https://doi.org/10.1002/ajmg.c.31435

75. Vergaelen, E., Swillen, A., Van Esch, H., et al., 3 generation pedigree with paternal transmission of the 22q11.2 deletion syndrome: intrafamilial phenotypic variability, Eur. J. Med. Genet., 2015, vol. 58, no. 4, pp. 244–248. https://doi.org/10.1016/j.ejmg.2015.01.008

76. Vogel, B.H., Bonagura, V., Weinberg, G.A., et al., Newborn screening for SCID in New York State: experience from the first two years, J. Clin. Immunol., 2014, vol. 34, no. 3, pp. 289–303. https://doi.org/10.1007/s10875-014-0006-7

77. Wong, M., Lambeck, A., Van der Burg, M., et al., Immune dysfunction in children with CHARGE syndrome: a cross-sectional study, PLoS One, 2015, vol. 10, no. 11, e0142350. https://doi.org/10.1371/journal.pone.0142350

78. Wu, Z.H., Phenotypes and genotypes of the chromosomal instability syndromes. Translat. Pediatr., 2016, vol. 5, no. 2, p. 79.

79. Wu, G.S. and Bassing, C.H., Inefficient V(D)J recombination underlies monogenic T cell receptor β expression, Proc. Natl. Acad. Sci. U. S. A., 2020, vol. 117, no. 31, pp. 18172–18174. https://doi.org/10.1073/pnas.2010077117

80. Yapijakis, C., Angelopoulou, A., Manolakos, E., Voumvourakis, C., et al., Craniofacial and neurological phenotype in a patient with de novo 18q microdeletion and 18p microduplication, Adv. Exp. Med. Biol., Springer, 2020, pp. 163–166. https://doi.org/10.1007/978-3-030-32633-3_22

81. Yarema, N., Fedortsiv, O., and Palasiuk, B., Influence of w-3 polyunsaturated fatty acids on the structure of immunocompetent cell membranes and the parameters of cellular and humoral immunity in children with rheumatoid arthritis, Fam. Med. Primary Care Rev., 2018, vol. 20, no. 1, pp. 78–82. https://doi.org/10.5114/fmpcr.2018.73707

82. Yazdani, R., Tavakol, M., Motlagh, A.V., Shafiei, A., Darougar, S., Chavoshzadeh, Z., and Ochs, H.D., Combined immunodeficiencies with associated or syndromic features, in Inborn Errors of Immunity, Academic, 2021, pp. 41–91.