Вопросы гематологии/онкологии и иммунопатологии в педиатрии. 2024; 23: 131-137
Особенности генетического разнообразия у пациентов детского возраста с врожденными дефектами иммунитета в России
https://doi.org/10.24287/1726-1708-2024-23-4-131-137Аннотация
На сегодняшний день известно около 500 генетических дефектов, обусловливающих клинические проявления иммунодефицитных состояний. Молекулярно-генетический диагноз необходим для определения тактики ведения пациента с врожденными дефектами иммунитета (ВДИ) и играет важную роль в семейном генетическом консультировании. В целях поиска генетической причины ВДИ были обследованы 2395 пробандов, из них у 1507 (65,7%) идентифицированы 164 нозологические формы ВДИ с дефектами в 143 уникальных генах и поломками 8 хромосом. Подавляющая часть ВДИ (89,1%) представлена моногенными повреждениями, из которых 98,6% имели герминальное происхождение. ВДИ вследствие крупных хромосомных поломок развили 10,6% пробандов. Наиболее часто встречающиеся моногенные формы ВДИ с подтвержденным генетическим дефектом представлены синдромом Вискотта–Олдрича, Х-сцепленной хронической гранулематозной болезнью, Х-сцепленной агаммаглобулинемией, синдромом Ниймеген, наследственным ангионевротическим отеком 1-го и 2-го типов, синдромом Луи–Бар, синдромом Швахмана–Даймонда, тяжелой врожденной нейтропенией, Х-сцепленной тяжелой комбинированной иммунной недостаточностью. Среди иммунодефицитов с хромосомными поломками преобладает синдром del22.q11.2 (синдром ДиДжорджи). Эти 10 нозологических форм ВДИ отмечены у 51% (775/1507) всех наблюдаемых пробандов с подтвержденным генетическим диагнозом. Особый интерес представляют 6,4% (96/1507) пробандов с уникальными случаями ВДИ, обнаруженными у 1–2 пациентов и представленными 80 различными нозологическими формами с поломками в 73 генах и 6 хромосомах. Среди них преобладают ВДИ с аутосомно-рецессивным типом наследования (65%), еще 30% наследуются аутосомно-доминантным путем и лишь 5% – Х-сцепленным. Кроме того, у 0,3% пробандов выявлены полигенные причины ВДИ, у 0,9% пробандов к ВДИ привели соматические повреждения известных генов (NRAS, KRAS, FAS, NLRP3). Частота семейных случаев среди пробандов с подтвержденным генетическим диагнозом составила 9,6% (145/1507). Понимание механизмов возникновения и наследования ВДИ в гетерогенной российской популяции окажет важную роль в разработке диагностических и терапевтических стратегий для пациентов и их семей. Данное исследование одобрено независимым этическим комитетом и утверждено решением ученого совета ФГБУ «НМИЦ ДГОИ им. Дмитрия Рогачева» Минздрава России. Информированное согласие на генетическое обследование и публикацию результатов было получено от пациентов и/или хотя бы одного из родителей детей, не достигших возраста согласия.
Список литературы
1. Tangye S.G., Al-Herz W., Bousfiha A., Cunningham-Rundles C., Franco J.L., Holland S.M., et al. Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol 2022; 42 (7): 1473–507. DOI: 10.1007/s10875-022-01289-3
2. Bousfiha A., Moundir A., Tangye S.G., Picard C., Jeddane L., Al-Herz W., et al. The 2022 Update of IUIS Phenotypical Classification for Human Inborn Errors of Immunity. J Clin Immunol 2022; 42 (7): 1508–20. DOI: 10.1007/s10875-022-01352-z
3. Notarangelo L.D., Sorensen R. Is it necessary to identify molecular defects in primary immunodeficiency disease? J Allergy Clin Immunol 2008; 122: 1069–73. DOI: 10.1016/j.jaci.2008.08.038
4. Abolhassani H., Azizi G., Sharifi L., Yazdani R., Mohsenzadegan M., Delavari S., et al. Global systematic review of primary immunodeficiency registries. Expert Rev Clin Immunol 2020; 16 (7): 717–32. DOI: 10.1080/1744666X.2020.1801422
5. El-Helou S.M., Biegner A.K., Bode S., Ehl S.R., Heeg M., Maccari M.E., et al. The German National registry of primary immunodeficiencies (2012–2017). Front Immunol 2019; 10: 1272. DOI: 10.3389/fimmu.2019.01272
6. Marschall K., Hoernes M., Bitzenhofer-Grüber M., Jandus P., Duppenthaler A., Wuillemin W.A., et al. The Swiss National Registry for Primary Immunodeficiencies: report on the first 6 years’ activity from 2008 to (2014). Clin Exp Immunol 2015; 182: 45–50. DOI: 10.1111/cei.12661
7. Naidoo R., Ungerer L., Cooper M., et al. Primary immunodeficiencies: a 27-year review at a tertiary paediatric hospital in Cape Town, South Africa. J Clin Immunol 2011; 31 (1): 99–105.
8. Deripapa E., Balashov D., Rodina Y., Laberko A., Myakova N., Davydova N.V., et al. Prospective Study of a Cohort of Russian Nijmegen Breakage Syndrome Patients Demonstrating Predictive Value of Low Kappa– Deleting Recombination Excision Circle (KREC) Numbers and Beneficial Effect of Hematopoietic Stem Cell Transplantation (HSCT). Front Immunol 2017; 8: 807. DOI: 10.3389/fimmu.2017.00807
9. Alghamdi M. Familial Mediterranean fever, review of the literature. Clin Rheumatol 2017; 36 (8): 1707–13. DOI: 10.1007/s10067-017-3715-5
10. European Society for Immunodeficiencies. Registry Working Party Diagnosis Criteria. (2018). [Electronic resource] URL: https://esid.org/Working-Parties/Registry-Working-Party/Diagnosis-criteria (accessed December 3, 2019).
11. Mukhina A.A., Kuzmenko N.B., Rodina Yu.A., Kondratenko I.V., Bologov A.A., Latysheva T.V., et al. Primary Immunodeficiencies in Russia: Data From the National Registry. Front Immunol 2020; 11: 1491. DOI: 10.3389/fimmu.2020.01491
12. Kuzmenko N., Alexenko M., Mukhina A., Rodina Y., Fadeeva M., Pershin D., et al. Genetic Characteristics of a Large Pediatric Cohort of Patients with Inborn Errors of Immunity: Single-Center Experience. J Clin Immunol 2024; 44: 165. DOI: 10.1007/s10875-024-01767-w
13. Jindal A.K., Pilania R.K., Rawat A., Singh S. Primary Immunodeficiency Disorders in India-A Situational Review. Front Immunol 2017; 8: 714. DOI: 10.3389/fimmu.2017.00714
14. Zakharova V., Raykina E., Mersiyanova I., Deordieva E., Pershin D., Vedmedskia V., et al. Cancer-causing MAP2K1 mutation in a mosaic patient with cardio-facio-cutaneous syndrome and immunodeficiency. Hum Mutat 2022; 43 (12): 1852–5. DOI: 10.1002/humu.24463
15. Терентьева А.И., Викторова Е.А., Захарова В.В., Коновалов Д.В., Бурлаков В.И., Родина Ю.А. и др. Клинический случай протеасом-ассоциированного аутовоспалительного синдрома 2-го типа (PRAAS2). Вопросы гематологии/ онкологии и иммунопатологии в педиатрии 2019; 18 (2): 108–13. DOI: 10.24287/1726-1708-2019-18-2-108-113
16. Le Coz C., Nguyen D.N., Su C., Nolan B.E., Albrecht A.V., Xhani S., et al. Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients. J Exp Med 2021; 218 (7): e20201750. DOI: 10.1084/jem.20201750
17. Maffucci P., Filion C.A., Boisson B., Itan Y., Shang L., Casanova J.-L., Cunningham-Rundles C. Genetic Diagnosis Using Whole Exome Sequencing in Common Variable Immunodeficiency. Front Immunol 2016; 7: 220. DOI: 10.3389/fimmu.2016.00220
18. Seleman M., Hoyos-Bachiloglu R., Geha R.S., Chou J. Uses of Next-Generation Sequencing Technologies for the Diagnosis of Primary Immunodeficiencies. Front Immunol 2017; 8: 847. DOI: 10.3389/fimmu.2017.00847
19. Seidel M.G., Kindle G., Gathmann B., Quinti I., Buckland M., van Montfrans J., et al. The European Society for Immunodeficiencies (ESID) Registry Working Definitions for the Clinical Diagnosis of Inborn Errors of Immunity. J Allergy Clin Immunol Pract 2019; 7 (6): 1763– 70. DOI: 10.1016/j.jaip.2019.02.004
20. Abraham R.S., Butte M.J. The New “Wholly Trinity” in the Diagnosis and Management of Inborn Errors of Immunity. J Allergy Clin Immunol Pract 2021; 9 (2): 613–25. DOI: 10.1016/j.jaip.2020.11.044
21. Al-Saud B., Al-Mousa H., Al Gazlan S., Al-Ghonaium A., Arnaout R., Al-Seraihy A., et al. Primary Immunodeficiency Diseases in Saudi Arabia: a Tertiary Care Hospital Experience over a Period of Three Years (2010–2013). J Clin Immunol 2015; 35 (7): 651–60.
22. Boocock G.R., Morrison J.A., Popovic M., Richards N., Ellis L., Durie P.R., Rommens J.M. Mutations in SBDS are associated with Shwachman–Diamond syndrome. Nat Genet 2003; 33 (1): 97–101. DOI: 10.1038/ng1062
23. Garelli S., Dalla Costa M., Sabbadin C., Barollo S., Rubin B., Scarpa R, et al. Autoimmune polyendocrine syndrome type 1: an Italian survey on 158 patients. J Endocrinol Invest 2021; 44: 2493–510. DOI: 10.1007/s40618-021-01585-6
24. Heino M., Peterson P., Kudoh J., Shimizu N., Antonarakis S.E., Scott H.S., et al. APECED mutations in the autoimmune regulator (AIRE) gene. Hum Mutat 2001; 18 (3): 205–11. DOI: 10.1002/humu.1176
25. Орлова Е.М., Созаева Л.С., Карманов М.Е., Брейвик Л., Хусби Э., Карева М.А. Новые иммунологические методы диагностики аутоиммунного полиэндокринного синдрома 1-го типа (первый опыт в России). Проблемы эндокринологии 2015; 61 (5): 9–13. DOI: 10.14341/probl20156159-13
Pediatric Hematology/Oncology and Immunopathology. 2024; 23: 131-137
Genetic diversity in pediatric patients with inborn errors of immunity in Russia
https://doi.org/10.24287/1726-1708-2024-23-4-131-137Abstract
To date, about 500 genetic defects are known to cause clinical manifestations of immunodeficiency. Genetic diagnosis is necessary to guide the management of patients with inborn errors of immunity (IEI) and plays an important role in genetic counselling of families. To find the genetic cause of IEI, 2395 probands were tested, in 1507 (65.7%) of them we identified 164 forms of IEI with defects in 143 single genes and abnormalities in 8 chromosomes. The majority of IEIs (89.1%) were monogenic, with 98.6% of them being of germline origin. Only 10.6% of IEIs were due to large chromosomal breaks. The most common monogenic forms of IEI with a confirmed genetic defect are Wiskott–Aldrich syndrome, X-linked chronic granulomatous disease, X-linked agammaglobulinemia, Nijmegen syndrome, hereditary angioedema types 1 and 2, ataxia-telangiectasia, Schwachman–Diamond syndrome, severe congenital neutropenia, X-linked severe combined immunodeficiency. Among IEIs associated with chromosomal abnormalities, del22.q11.2 syndrome (DiGeorge syndrome) predominates. These 10 forms of IEI were detected in 51% (775/1507) of all the probands with a confirmed genetic diagnosis. In our study, 6.4% (96/1507) of the probands had unique IEIs: a total of 80 different IEI entities associated with defects in 73 genes and 6 chromosomes (each entity affecting 1 or 2 patients). The majority of them were autosomal recessive IEIs (65%), 30% were autosomal dominant, and only 5% of the cases were X-linked. In addition, polygenic IEIs were identified in 0.3% of the probands and somatic mutations in wellknown genes (NRAS, KRAS, FAS, NLRP3) led to IEI in 0.9% of the probands. The frequency of familial cases among the probands with a confirmed genetic diagnosis was 9.6% (145/1507). Understanding the mechanisms of occurrence and inheritance of IEI in the heterogeneous Russian population will play an important role in the development of diagnostic and therapeutic strategies for patients and their families. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation. Informed consent for genetic testing and for the publication of its results was obtained from the patients and/or from at least one parent of a child under the age of consent.
References
1. Tangye S.G., Al-Herz W., Bousfiha A., Cunningham-Rundles C., Franco J.L., Holland S.M., et al. Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol 2022; 42 (7): 1473–507. DOI: 10.1007/s10875-022-01289-3
2. Bousfiha A., Moundir A., Tangye S.G., Picard C., Jeddane L., Al-Herz W., et al. The 2022 Update of IUIS Phenotypical Classification for Human Inborn Errors of Immunity. J Clin Immunol 2022; 42 (7): 1508–20. DOI: 10.1007/s10875-022-01352-z
3. Notarangelo L.D., Sorensen R. Is it necessary to identify molecular defects in primary immunodeficiency disease? J Allergy Clin Immunol 2008; 122: 1069–73. DOI: 10.1016/j.jaci.2008.08.038
4. Abolhassani H., Azizi G., Sharifi L., Yazdani R., Mohsenzadegan M., Delavari S., et al. Global systematic review of primary immunodeficiency registries. Expert Rev Clin Immunol 2020; 16 (7): 717–32. DOI: 10.1080/1744666X.2020.1801422
5. El-Helou S.M., Biegner A.K., Bode S., Ehl S.R., Heeg M., Maccari M.E., et al. The German National registry of primary immunodeficiencies (2012–2017). Front Immunol 2019; 10: 1272. DOI: 10.3389/fimmu.2019.01272
6. Marschall K., Hoernes M., Bitzenhofer-Grüber M., Jandus P., Duppenthaler A., Wuillemin W.A., et al. The Swiss National Registry for Primary Immunodeficiencies: report on the first 6 years’ activity from 2008 to (2014). Clin Exp Immunol 2015; 182: 45–50. DOI: 10.1111/cei.12661
7. Naidoo R., Ungerer L., Cooper M., et al. Primary immunodeficiencies: a 27-year review at a tertiary paediatric hospital in Cape Town, South Africa. J Clin Immunol 2011; 31 (1): 99–105.
8. Deripapa E., Balashov D., Rodina Y., Laberko A., Myakova N., Davydova N.V., et al. Prospective Study of a Cohort of Russian Nijmegen Breakage Syndrome Patients Demonstrating Predictive Value of Low Kappa– Deleting Recombination Excision Circle (KREC) Numbers and Beneficial Effect of Hematopoietic Stem Cell Transplantation (HSCT). Front Immunol 2017; 8: 807. DOI: 10.3389/fimmu.2017.00807
9. Alghamdi M. Familial Mediterranean fever, review of the literature. Clin Rheumatol 2017; 36 (8): 1707–13. DOI: 10.1007/s10067-017-3715-5
10. European Society for Immunodeficiencies. Registry Working Party Diagnosis Criteria. (2018). [Electronic resource] URL: https://esid.org/Working-Parties/Registry-Working-Party/Diagnosis-criteria (accessed December 3, 2019).
11. Mukhina A.A., Kuzmenko N.B., Rodina Yu.A., Kondratenko I.V., Bologov A.A., Latysheva T.V., et al. Primary Immunodeficiencies in Russia: Data From the National Registry. Front Immunol 2020; 11: 1491. DOI: 10.3389/fimmu.2020.01491
12. Kuzmenko N., Alexenko M., Mukhina A., Rodina Y., Fadeeva M., Pershin D., et al. Genetic Characteristics of a Large Pediatric Cohort of Patients with Inborn Errors of Immunity: Single-Center Experience. J Clin Immunol 2024; 44: 165. DOI: 10.1007/s10875-024-01767-w
13. Jindal A.K., Pilania R.K., Rawat A., Singh S. Primary Immunodeficiency Disorders in India-A Situational Review. Front Immunol 2017; 8: 714. DOI: 10.3389/fimmu.2017.00714
14. Zakharova V., Raykina E., Mersiyanova I., Deordieva E., Pershin D., Vedmedskia V., et al. Cancer-causing MAP2K1 mutation in a mosaic patient with cardio-facio-cutaneous syndrome and immunodeficiency. Hum Mutat 2022; 43 (12): 1852–5. DOI: 10.1002/humu.24463
15. Terent'eva A.I., Viktorova E.A., Zakharova V.V., Konovalov D.V., Burlakov V.I., Rodina Yu.A. i dr. Klinicheskii sluchai proteasom-assotsiirovannogo autovospalitel'nogo sindroma 2-go tipa (PRAAS2). Voprosy gematologii/ onkologii i immunopatologii v pediatrii 2019; 18 (2): 108–13. DOI: 10.24287/1726-1708-2019-18-2-108-113
16. Le Coz C., Nguyen D.N., Su C., Nolan B.E., Albrecht A.V., Xhani S., et al. Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients. J Exp Med 2021; 218 (7): e20201750. DOI: 10.1084/jem.20201750
17. Maffucci P., Filion C.A., Boisson B., Itan Y., Shang L., Casanova J.-L., Cunningham-Rundles C. Genetic Diagnosis Using Whole Exome Sequencing in Common Variable Immunodeficiency. Front Immunol 2016; 7: 220. DOI: 10.3389/fimmu.2016.00220
18. Seleman M., Hoyos-Bachiloglu R., Geha R.S., Chou J. Uses of Next-Generation Sequencing Technologies for the Diagnosis of Primary Immunodeficiencies. Front Immunol 2017; 8: 847. DOI: 10.3389/fimmu.2017.00847
19. Seidel M.G., Kindle G., Gathmann B., Quinti I., Buckland M., van Montfrans J., et al. The European Society for Immunodeficiencies (ESID) Registry Working Definitions for the Clinical Diagnosis of Inborn Errors of Immunity. J Allergy Clin Immunol Pract 2019; 7 (6): 1763– 70. DOI: 10.1016/j.jaip.2019.02.004
20. Abraham R.S., Butte M.J. The New “Wholly Trinity” in the Diagnosis and Management of Inborn Errors of Immunity. J Allergy Clin Immunol Pract 2021; 9 (2): 613–25. DOI: 10.1016/j.jaip.2020.11.044
21. Al-Saud B., Al-Mousa H., Al Gazlan S., Al-Ghonaium A., Arnaout R., Al-Seraihy A., et al. Primary Immunodeficiency Diseases in Saudi Arabia: a Tertiary Care Hospital Experience over a Period of Three Years (2010–2013). J Clin Immunol 2015; 35 (7): 651–60.
22. Boocock G.R., Morrison J.A., Popovic M., Richards N., Ellis L., Durie P.R., Rommens J.M. Mutations in SBDS are associated with Shwachman–Diamond syndrome. Nat Genet 2003; 33 (1): 97–101. DOI: 10.1038/ng1062
23. Garelli S., Dalla Costa M., Sabbadin C., Barollo S., Rubin B., Scarpa R, et al. Autoimmune polyendocrine syndrome type 1: an Italian survey on 158 patients. J Endocrinol Invest 2021; 44: 2493–510. DOI: 10.1007/s40618-021-01585-6
24. Heino M., Peterson P., Kudoh J., Shimizu N., Antonarakis S.E., Scott H.S., et al. APECED mutations in the autoimmune regulator (AIRE) gene. Hum Mutat 2001; 18 (3): 205–11. DOI: 10.1002/humu.1176
25. Orlova E.M., Sozaeva L.S., Karmanov M.E., Breivik L., Khusbi E., Kareva M.A. Novye immunologicheskie metody diagnostiki autoimmunnogo poliendokrinnogo sindroma 1-go tipa (pervyi opyt v Rossii). Problemy endokrinologii 2015; 61 (5): 9–13. DOI: 10.14341/probl20156159-13
