vspВопросы современной педиатрииCurrent Pediatrics1682-55271682-5535Издательство «ПедиатрЪ»10.15690/vsp.v23i2.2725vsp-3454Research ArticleКЛИНИЧЕСКОЕ НАБЛЮДЕНИЕCLINICAL OBSERVATIONSБолезнь Вильсона, вызванная ранее не описанным гомозиготным нуклеотидным вариантом гена ATP7B: клинические случаиWilson’s Disease Caused by Previously Undescribed Homozygous Nucleotide Variant of the ATP7B Gene: Clinical Caseshttps://orcid.org/0000-0002-9734-017XЧерневскийД. К.ChernevskiyDenis K.

Черневский Денис Константинович, врач-генетик Университетской клиники ПИМУ; врач-генетик ООО «Эвоген».

603950, БОКС-470, Нижний Новгород, пл. Минина и Пожарского, д. 10/1

Тел.: +7 (831) 439-09-43

Nizhny Novgorod; Moscow

dk_ch@mail.ruhttps://orcid.org/0000-0002-0447-214XЛавроваА. Е.LavrovaAlla E.

Нижний Новгород

Nizhny Novgorod

https://orcid.org/0000-0003-1059-6293КоноваловаЕ. Ю.KonovalovaEkaterina Yu.

Нижний Новгород

Nizhny Novgorod

https://orcid.org/0000-0002-8273-9858БорисоваЕ. Ю.BorisovaElena Yu.

Нижний Новгород

Nizhny Novgorod

https://orcid.org/0000-0003-2258-6463ДорощукН. А.DoroshchukNatalia A.

Москва

Moscow

https://orcid.org/0000-0002-7511-3240ГрозноваО. С.GroznovaOlga S.

Москва

Moscow

Приволжский исследовательский медицинский университет; ООО «Эвоген»РоссияPrivolzhsky Research Medical University; EvogenRussian FederationПриволжский исследовательский медицинский университетРоссияPrivolzhsky Research Medical UniversityRussian FederationООО «Эвоген»РоссияEvogenRussian FederationБлаготворительный фонд медико-социальных генетических проектов помощи «Геном жизни»; РНИМУ им. Н.И. ПироговаРоссияCharity Fund for Medical and Social Genetic Aid Projects “Life Genome”; Pirogov Russian National Research Medical UniversityRussian Federation202405052024232104110Copyright © Черневский Д.К., Лаврова А.Е., Коновалова Е.Ю., Борисова Е.Ю., Дорощук Н.А., Грознова О.С., 20242024Черневский Д.К., Лаврова А.Е., Коновалова Е.Ю., Борисова Е.Ю., Дорощук Н.А., Грознова О.С.Chernevskiy D.K., Lavrova A.E., Konovalova E.Y., Borisova E.Y., Doroshchuk N.A., Groznova O.S.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://vsp.spr-journal.ru/jour/article/view/3454

Обоснование. Болезнь Вильсона — тяжелое аутосомно-рецессивное заболевание, проявляющееся преимущественно печеночными, неврологическими и психиатрическими нарушениями вследствие чрезмерного отложения меди в органах и тканях. Описание клинического случая. Описан вариант неопределенного клинического значения c.2111C>T (p.T704I, chr13:52534294G>A (HG19)) гена ATP7B в семье, в которой родители являются двоюродными сибсами. Из четырех детей старшая дочь погибла в возрасте 11 лет в связи с циррозом печени, у двоих детей генетически подтверждена болезнь Вильсона (клинически — абдоминальная форма), у младшего сына вариант выявлен в гетерозиготном состоянии (без клинических проявлений). Обнаруженный вариант гена ATP7B ранее был выявлен еще у 3 пациентов с болезнью Вильсона, но в компаунд-гетерозиготном состоянии с известным патогенным генетическим вариантом. Заключение. Вариант c.2111C>T (p.T704I) гена ATP7B можно рассматривать как вероятно патогенный. Необходимы дальнейшие исследования его функционального значения в патогенезе болезни Вильсона.

Wilson’s disease is severe autosomal recessive disease manifested primarily by hepatic, neurological, and psychiatric disorders due to excessive copper deposition in organs and tissues. Clinical case description. The variant with uncertain clinical value of the ATP7B gene, c.2111C>T (p.T704I, chr13:52534294G>A (HG19)), was described in the family where parents are cousins. The eldest daughter out of four children died at the age of 11 due to liver cirrhosis. Wilson’s disease was genetically confirmed in two children (clinically — abdominal form). The younger son was diagnosed heterozygous state of the disease (without any clinical manifestations). The revealed variant of the ATP7B gene was previously identified in 3 more patients with Wilson’s disease, however, in a compound heterozygous state with known pathogenic genetic variant. Conclusion. c.2111C>T (p.T704I) variant of the ATP7B gene can be considered as probably pathogenic. Further research is required to evaluate its functional significance in Wilson’s disease pathogenesis.

детиболезнь Вильсонасемейный случайген ATP7Bциррозполногеномное секвенированиеchildrenWilson’s diseasefamilial caseATP7B genecirrhosiswhole-genome sequencingПолногеномное и валидационное секвенирование по Сенгеру было проведено с использованием финансовых средств благотворительного фонда медико-социальных генетических проектов помощи «Геном жизни».Whole-genome and validation Sanger sequencing was performed with the help of Charity Fund for Medical and Social Genetic Aid Projects “Life Genome”.ReferencesTrocello JM, Broussolle E, Girardot-Tinant N, et al. Wilson’s disease, 100 years later… Rev Neurol (Paris). 2013;169(12):936–943. doi: https//doi.org/10.1016/j.neurol.2013.05.002Trocello JM, Broussolle E, Girardot-Tinant N, et al. Wilson’s disease, 100 years later… Rev Neurol (Paris). 2013;169(12):936–943. doi: https//doi.org/10.1016/j.neurol.2013.05.002Weiss KH, Schilsky M. Wilson Disease. 1999 Oct 22 [updated 2023 Jan 12]. In: GeneReviews® [Internet]. Adam MP, Mirzaa GM, Pagon RA, et al., eds. Seattle (WA): University of Washington, Seattle; 1993–2023.Weiss KH, Schilsky M. Wilson Disease. 1999 Oct 22 [updated 2023 Jan 12]. In: GeneReviews® [Internet]. Adam MP, Mirzaa GM, Pagon RA, et al., eds. Seattle (WA): University of Washington, Seattle; 1993–2023.Gomes A, Dedoussis GV. Geographic distribution of ATP7B mutations in Wilson disease. Ann Hum Biol. 2016;43(1):1–8. doi: https//doi.org/10.3109/03014460.2015.1051492Gomes A, Dedoussis GV. Geographic distribution of ATP7B mutations in Wilson disease. Ann Hum Biol. 2016;43(1):1–8. doi: https//doi.org/10.3109/03014460.2015.1051492Баязутдинова Г.М., Щагина О.А., Карунас А.С. и др. Спектр мутаций в гене ATP7B у российских больных с болезнью Вильсона–Коновалова // Генетика. — 2019. — Т. 55. — № 12. — С. 1433–1441. — doi: https//doi.org/10.1134/S0016675819120026Bayazutdinova GM, Shchagina OA, Polyakov AV, et al. Spectrum of Mutations in the ATP7B Gene in Russian Patients with Wilson’s. Russian Journal of Genetics. 2019;55(12):1433–1441. (In Russ). doi: https//doi.org/10.1134/S0016675819120026Mulligan C, Bronstein JM. Wilson Disease: An Overview and Approach to Management. Neurol Clin. 2020;38(2):417–432. doi: https//doi.org/10.1016/j.ncl.2020.01.005Mulligan C, Bronstein JM. Wilson Disease: An Overview and Approach to Management. Neurol Clin. 2020;38(2):417–432. doi: https//doi.org/10.1016/j.ncl.2020.01.005Лузина Е.В., Емельянова О.Н., Щербак В.А. и др. Болезнь Вильсона: обзор клинических рекомендаций, литературных данных и собственное наблюдение // Экспериментальная и клиническая гастроэнтерология. — 2022. — № 7. — С. 239–245. — doi: https://doi.org/10.31146/1682-8658-ecg-203-7-239-245Luzina EV, Yemelyanova ON, Shcherbak VA, et al. Wilson’s disease: a review of clinical guidelines, literature and a case report. Experimental and Clinical Gastroenterology. 2022;(7):239–245. (In Russ). doi: https://doi.org/10.31146/1682-8658-ecg-203-7-239-245Członkowska A, Litwin T, Dusek P, et al. Wilson disease. Nat Rev Dis Primers. 2018;4(1):21. doi: https://doi.org/10.1038/s41572-018-0018-3Członkowska A, Litwin T, Dusek P, et al. Wilson disease. Nat Rev Dis Primers. 2018;4(1):21. doi: https://doi.org/10.1038/s41572-018-0018-3Нарушения обмена меди (болезнь Вильсона): клинические рекомендации / Ассоциация медицинских генетиков; Союз педиатров России; Некоммерческое Партнерство «Национальное общество по изучению болезни Паркинсона и расстройств движений»; Российское трансплантологическое общество; Автономная некоммерческая организация «Общество детских гастроэнтерологов, гепатологов и нутрициологов»; Национальная ассоциация детских реабилитологов. — Минздрав России; 2021. — 66 с.Narusheniya obmena medi (bolezn’ Vil’sona): Clinical Guidelines. Association of Medical Genetics; Union of Pediatricians of Russia; Non-profit Partnership “National Society for the Study of Parkinson’s Disease and Movement Disorders”; Russian Transplant Society; Autonomous non-profit organization “Society of Pediatric Gastroenterologists, Hepatologists and Nutritionists”; National Association of Children’s Rehabilitologists. Ministry of Health of Russia; 2021. 66 p. (In Russ).European Association for Study of Liver. EASL Clinical Practice Guidelines: Wilson’s disease. J Hepatol. 2012;56(3):671–685. doi: https://doi.org/10.1016/j.jhep.2011.11.007European Association for Study of Liver. EASL Clinical Practice Guidelines: Wilson’s disease. J Hepatol. 2012;56(3):671–685. doi: https://doi.org/10.1016/j.jhep.2011.11.007Saroli Palumbo C, Schilsky ML. Clinical practice guidelines in Wilson disease. Ann Transl Med. 2019;7(Suppl 2):S65. doi: https://doi.org/10.21037/atm.2018.12.53Saroli Palumbo C, Schilsky ML. Clinical practice guidelines in Wilson disease. Ann Transl Med. 2019;7(Suppl 2):S65. doi: https://doi.org/10.21037/atm.2018.12.53Koboldt DC, Hickey SE, Chaudhari BP, et al. Early-onset Wilson disease caused by ATP7B exon skipping associated with intronic variant. Cold Spring Harb Mol Case Stud. 2020;6(3):a005306. doi: https://doi.org/10.1101/mcs.a005306Koboldt DC, Hickey SE, Chaudhari BP, et al. Early-onset Wilson disease caused by ATP7B exon skipping associated with intronic variant. Cold Spring Harb Mol Case Stud. 2020;6(3):a005306. doi: https://doi.org/10.1101/mcs.a005306Xu WQ, Wang RM, Dong Y, Wu ZY. Pathogenicity of Intronic and Synonymous Variants of ATP7B in Wilson Disease. J Mol Diagn. 2023;25(1):57–67. doi: https://doi.org/10.1016/j.jmoldx.2022.10.002Xu WQ, Wang RM, Dong Y, Wu ZY. Pathogenicity of Intronic and Synonymous Variants of ATP7B in Wilson Disease. J Mol Diagn. 2023;25(1):57–67. doi: https://doi.org/10.1016/j.jmoldx.2022.10.002Kerkar N, Rana A. Wilson Disease in Children. Clin Liver Dis. 2022;26(3):473–488. doi: https://doi.org/10.1016/j.cld.2022.03.008Kerkar N, Rana A. Wilson Disease in Children. Clin Liver Dis. 2022;26(3):473–488. doi: https://doi.org/10.1016/j.cld.2022.03.008De Rycke M, Berckmoes V. Preimplantation Genetic Testing for Monogenic Disorders. Genes (Basel). 2020;11(8):871. doi: https://doi.org/10.3390/genes11080871De Rycke M, Berckmoes V. Preimplantation Genetic Testing for Monogenic Disorders. Genes (Basel). 2020;11(8):871. doi: https://doi.org/10.3390/genes11080871Li M, Ma J, Wang W, et al. Mutation analysis of the ATP7B gene and genotype-phenotype correlation in Chinese patients with Wilson disease. BMC Gastroenterol. 2021;21(1):339. doi: https://doi.org/10.1186/s12876-021-01911-5Li M, Ma J, Wang W, et al. Mutation analysis of the ATP7B gene and genotype-phenotype correlation in Chinese patients with Wilson disease. BMC Gastroenterol. 2021;21(1):339. doi: https://doi.org/10.1186/s12876-021-01911-5Bennett RL, French KS, Resta RG, Austin J. Practice resource-focused revision: Standardized pedigree nomenclature update centered on sex and gender inclusivity: A practice resource of the National Society of Genetic Counselors. J Genet Couns. 2022;31(6):1238–1248. doi: https://doi.org/10.1002/jgc4.1621Bennett RL, French KS, Resta RG, Austin J. Practice resource-focused revision: Standardized pedigree nomenclature update centered on sex and gender inclusivity: A practice resource of the National Society of Genetic Counselors. J Genet Couns. 2022;31(6):1238–1248. doi: https://doi.org/10.1002/jgc4.1621Variant chr13-52534294-G-A. In: Varsome. Available online: https://varsome.com/variant/hg19/chr13-52534294-G-A?annotation-mode=germline. Accessed on January 08, 2024.Variant chr13-52534294-G-A. In: Varsome. Available online: https://varsome.com/variant/hg19/chr13-52534294-G-A?annotation-mode=germline. Accessed on January 08, 2024.Variant T704I. In: WilsonGen. Available online: https://clingen.igib.res.in/WilsonGen/showdata.php?id=5e9b367b3a6e8b628a865239&hgvs_id=&Start=52534294&Alt=A&Ref=G&chr=chr13. Accessed on January 08, 2024.Variant T704I. In: WilsonGen. Available online: https://clingen. igib.res.in/WilsonGen/showdata.php?id=5e9b367b3a6e8b628a865239&hgvs_id=&Start=52534294&Alt=A&Ref=G&chr=chr13. Accessed on January 08, 2024.Li X, Lu Z, Lin Y, et al. Clinical features and mutational analysis in 114 young children with Wilson disease from South China. Am J Med Genet A. 2019;179(8):1451–1458. doi: https://doi.org/10.1002/ajmg.a.61254Li X, Lu Z, Lin Y, et al. Clinical features and mutational analysis in 114 young children with Wilson disease from South China. Am J Med Genet A. 2019;179(8):1451–1458. doi: https://doi.org/10.1002/ajmg.a.61254Huang C, Fang M, Xiao X, et al. Genetic studies discover novel coding and non-coding mutations in patients with Wilson’s disease in China. J Clin Lab Anal. 2022;36(6):e24459. doi: https://doi.org/10.1002/jcla.24459Huang C, Fang M, Xiao X, et al. Genetic studies discover novel coding and non-coding mutations in patients with Wilson’s disease in China. J Clin Lab Anal. 2022;36(6):e24459. doi: https://doi.org/10.1002/jcla.24459Feng CX, Chen XQ, He XL, et al. Screening for Wilson’s disease in acute liver failure: A new scoring system in children. Front Pediatr. 2022;10:1003887. doi: https://doi.org/10.3389/fped.2022.1003887Feng CX, Chen XQ, He XL, et al. Screening for Wilson’s disease in acute liver failure: A new scoring system in children. Front Pediatr. 2022;10:1003887. doi: https://doi.org/10.3389/fped.2022.1003887Woimant F, Poujois A, Bloch A, et al. A novel deep intronic variant in ATP7B in five unrelated families affected by Wilson disease. Mol Genet Genomic Med. 2020;8(10):e1428. doi: https://doi.org/10.1002/mgg3.1428Woimant F, Poujois A, Bloch A, et al. A novel deep intronic variant in ATP7B in five unrelated families affected by Wilson disease. Mol Genet Genomic Med. 2020;8(10):e1428. doi: https://doi.org/10.1002/mgg3.1428Stalke A, Behrendt A, Hennig F, et al. Functional characterization of novel or yet uncharacterized ATP7B missense variants detected in patients with clinical Wilson’s disease. Clin Genet. 2023;104(2):174–185. doi: https://doi.org/10.1111/cge.14352Stalke A, Behrendt A, Hennig F, et al. Functional characterization of novel or yet uncharacterized ATP7B missense variants detected in patients with clinical Wilson’s disease. Clin Genet. 2023;104(2):174–185. doi: https://doi.org/10.1111/cge.14352Tang S, Bai L, Zheng SJ. Zhonghua Gan Zang Bing Za Zhi. 2021;29(1):21–24. doi: https://doi.org/10.3760/cma.j.cn501113-20201104-00598Tang S, Bai L, Zheng SJ. Zhonghua Gan Zang Bing Za Zhi. 2021;29(1):21–24. doi: https://doi.org/10.3760/cma.j.cn501113-20201104-00598Cai H, Cheng X, Wang XP. ATP7B gene therapy of autologous reprogrammed hepatocytes alleviates copper accumulation in a mouse model of Wilson’s disease. Hepatology. 2022;76(4):1046–1057. doi: https://doi.org/10.1002/hep.32484Cai H, Cheng X, Wang XP. ATP7B gene therapy of autologous reprogrammed hepatocytes alleviates copper accumulation in a mouse model of Wilson’s disease. Hepatology. 2022;76(4):1046–1057. doi: https://doi.org/10.1002/hep.32484Bittles AH, Black ML. Evolution in health and medicine Sackler colloquium: Consanguinity, human evolution, and complex diseases. Proc Natl Acad Sci U S A. 2010;107(Suppl 1):1779–1786. doi: https://doi.org/10.1073/pnas.0906079106Bittles AH, Black ML. Evolution in health and medicine Sackler colloquium: Consanguinity, human evolution, and complex diseases. Proc Natl Acad Sci U S A. 2010;107(Suppl 1):1779–1786. doi: https://doi.org/10.1073/pnas.0906079106Bennett RL, Malleda NR, Byers PH, et al. Genetic counseling and screening of consanguineous couples and their offspring practice resource: Focused Revision. J Genet Couns. 2021;30(5):1354–1357. doi: https://doi.org/10.1002/jgc4.1477Bennett RL, Malleda NR, Byers PH, et al. Genetic counseling and screening of consanguineous couples and their offspring practice resource: Focused Revision. J Genet Couns. 2021;30(5):1354–1357. doi: https://doi.org/10.1002/jgc4.1477

The authors declare that there are no conflicts of interest present.