medgenМедицинская генетикаMedical Genetics2073-7998Publishing House «Genius Media» LLC10.25557/2073-7998.2026.02.50-54medgen-3397Research ArticleКРАТКИЕ СООБЩЕНИЯBRIEF REPORTРедкие варианты гена WFS1 у лиц с фенотипом моногенного сахарного диабетаRare WFS1 Variants in Individuals with a Monogenic Diabetes PhenotypeИванощукД. Е.IvanoshchukD. E.

630090, г. Новосибирск, Россия, пр-т Академика Лаврентьева, д.10630004, г. Новосибирск, Россия, ул. Бориса Богаткова 175/1 

10, Prospekt Lavrentyeva, Novosibirsk, 630090, Russian Federation

175/1, Bogatkova st., Novosibirsk, 630004, Russian Federation 

dinara2084@mail.ruОвсянниковаА. К.OvsyannikovaA. K.

630004, г. Новосибирск, Россия, ул. Бориса Богаткова 175/1 

175/1, Bogatkova st., Novosibirsk, 630004, Russian Federation 

РымарО. Д.RymarO. D.

630004, г. Новосибирск, Россия, ул. Бориса Богаткова 175/1 

175/1, Bogatkova st., Novosibirsk, 630004, Russian Federation 

ОрловП. С.OrlovP. S.

630090, г. Новосибирск, Россия, пр-т Академика Лаврентьева, д.10

630004, г. Новосибирск, Россия, ул. Бориса Богаткова 175/1 

10, Prospekt Lavrentyeva, Novosibirsk, 630090, Russian Federation

175/1, Bogatkova st., Novosibirsk, 630004, Russian Federation 

ШахтшнейдерЕ. В.ShakhtshneiderE. V.

630090, г. Новосибирск, Россия, пр-т Академика Лаврентьева, д.10

630004, г. Новосибирск, Россия, ул. Бориса Богаткова 175/1 

10, Prospekt Lavrentyeva, Novosibirsk, 630090, Russian Federation

175/1, Bogatkova st., Novosibirsk, 630004, Russian Federation 

ФГБНУ Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наук; Научно-исследовательский институт терапии и профилактической медицины – филиал ФГБНУ Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наукРоссияFederal research center Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences; Institute of Internal and Preventive Medicine – branch of Institute of Cytology and Genetics, Siberian Branch of Russian Academy of SciencesRussian FederationНаучно-исследовательский институт терапии и профилактической медицины – филиал ФГБНУ Федеральный исследовательский центр Институт цитологии и генетики Сибирского отделения Российской академии наукРоссияInstitute of Internal and Preventive Medicine – branch of Institute of Cytology and Genetics, Siberian Branch of Russian Academy of SciencesRussian Federation2026160320262525054Copyright © Иванощук Д.Е., Овсянникова А.К., Рымар О.Д., Орлов П.С., Шахтшнейдер Е.В., 20262026Иванощук Д.Е., Овсянникова А.К., Рымар О.Д., Орлов П.С., Шахтшнейдер Е.В.Ivanoshchuk D.E., Ovsyannikova A.K., Rymar O.D., Orlov P.S., Shakhtshneider E.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.medgen-journal.ru/jour/article/view/3397

Патогенные варианты в гене WFS1 играют ключевую роль в этиологии синдрома Вольфрама – редкого наследственного заболевания, характеризующегося инсулинозависимым сахарным диабетом, атрофией зрительного нерва и рядом других клинических проявлений, тяжесть которых может различаться. В исследование были включены 518 человек: 318 неродственных пациентов с фенотипом моногенного сахарного диабета и 200 их кровных родственников. С использованием технологии секвенирования нового поколения выявлены редкие варианты в гене WFS1 (c.1943G>A (p.Trp648*), c.2225G>A (p.Cys742Tyr), c.1124G>A (p.Arg375His) и c.1336A>C (p.Ser446Arg)). Клиническая картина у пациентов варьировала от изолированного сахарного диабета до сочетания эндокринных, сенсорных и неврологических нарушений при носительстве одного и того же варианта. Полученные данные указывают на выраженную фенотипическую гетерогенность и необходимость комплексного подхода к диагностике моногенных форм сахарного диабета, включающего расширенное клиническое обследование и интерпретацию результатов генетического тестирования.

Pathogenic variants in the WFS1 gene play a key role in the etiology of Wolfram syndrome, a rare hereditary disorder characterized by insulin-dependent diabetes mellitus, optic nerve atrophy, and various additional clinical manifestations of highly variable severity. The study included 518 individuals: 318 unrelated patients with a monogenic diabetes phenotype and 200 biological relatives of the patients. Using next-generation sequencing, we identified rare WFS1 gene variants (c.1943G>A (p.Trp648*), c.2225G>A (p.Cys742Tyr), c.1124G>A (p.Arg375His) и c.1336A>C (p.Ser446Arg)). The clinical presentation among patients ranged from isolated diabetes mellitus to a combination of endocrine, sensory, and neurological impairments in carriers of the same variant. These findings highlight marked phenotypic heterogeneity and underscore the necessity of a comprehensive diagnostic approach to monogenic diabetes, incorporating thorough clinical evaluation and careful interpretation of genetic testing results.

синдром Вольфрамаген WFS1сахарный диабетмоногенные заболеванияWolfram syndromeWFS1 genediabetes mellitusmonogenic diseasesИсследование выполнено в рамках бюджетного проекта FWNR-2022-0021.This study was supported by the budget project FWNR-2022-0021ReferencesYamada T., Ishihara H., Tamura A., et al. WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic beta-cells. Hum Mol Genet. 2006;15(10):1600-9.Yamada T., Ishihara H., Tamura A., et al. WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic beta-cells. Hum Mol Genet. 2006;15(10):1600-9.Дедов И.И., Белая Ж.Е., Никонова Т.В., Смирнова О.М. Генетические синдромы, ассоциированные с сахарным диабетом: синдром Вольфрама. Проблемы Эндокринологии. 2005;51(5):52-55.Dedov I.I., Belaya Zh.Ye., Nikonova T.V., Smirnova О.М. Geneticheskiye sindromy, assotsiirovannyye s sakharnym diabetom: sindrom Vol’frama [Diabetes mellitus-associated genetic syndromes: Wolfram’s syndrome]. Problemy Endokrinologii [Problems of Endocrinology]. 2005;51(5):52-55. (In Russ.) https://doi.org/10.14341/probl200551552-55.Barrett T.G., Bundey S.E., Macleod A.F. Neurodegeneration and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndrome. Lancet. 1995;346(8988):1458-63.Barrett T.G., Bundey S.E., Macleod A.F. Neurodegeneration and diabetes: UK nationwide study of Wolfram (DIDMOAD) syndrome. Lancet. 1995;346(8988):1458-63.Pilley S.F., Thompson H.S.. Familial syndrome of diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (didmoad) in childhood. Br J Ophthalmol.1976;(60):294–298.Pilley S.F., Thompson H.S.. Familial syndrome of diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (didmoad) in childhood. Br J Ophthalmol.1976;(60):294–298.Gong Y., Xiong L., Li X., et al. A novel mutation of WFS1 gene leading to increase ER stress and cell apoptosis is associated an autosomal dominant form of Wolfram syndrome type 1. BMC Endocr Disord. 2021;21(1):76.Gong Y., Xiong L., Li X., et al. A novel mutation of WFS1 gene leading to increase ER stress and cell apoptosis is associated an autosomal dominant form of Wolfram syndrome type 1. BMC Endocr Disord. 2021;21(1):76.Morikawa S., Tajima T., Nakamura A., et al. A novel heterozygous mutation of the WFS1 gene leading to constitutive endoplasmic reticulum stress is the cause of Wolfram syndrome. Pediatr Diabetes. 2017;18(8):934-941.Morikawa S., Tajima T., Nakamura A., et al. A novel heterozygous mutation of the WFS1 gene leading to constitutive endoplasmic reticulum stress is the cause of Wolfram syndrome. Pediatr Diabetes. 2017;18(8):934-941.Bonnycastle L.L., Chines P.S., Hara T., et al. Autosomal dominant diabetes arising from a Wolfram syndrome 1 mutation. Diabetes. 2013;62(11):3943-50.Bonnycastle L.L., Chines P.S., Hara T., et al. Autosomal dominant diabetes arising from a Wolfram syndrome 1 mutation. Diabetes. 2013;62(11):3943-50.American Diabetes Association. Standards of medical care in diabetes-2013. Diabetes Care. 2013;(36):11-66.American Diabetes Association. Standards of medical care in diabetes-2013. Diabetes Care. 2013;(36):11-66.Richards S., Aziz N., Bale S., et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;(17):405–423.Richards S., Aziz N., Bale S., et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;(17):405–423.Li Y., Gong S., Li M., et al. The genetic and clinical characteristics of WFS1 related diabetes in Chinese early onset type 2 diabetes. Sci Rep. 2023;13(1):9127.Li Y., Gong S., Li M., et al. The genetic and clinical characteristics of WFS1 related diabetes in Chinese early onset type 2 diabetes. Sci Rep. 2023;13(1):9127.Zhu M., Li Y., Dong G., et al. Prevalence and phenotypic features of diabetes due to recessive, non-syndromic WFS1 mutations. Eur J Endocrinol. 2021;186 (2):163-170. .Zhu M., Li Y., Dong G., et al. Prevalence and phenotypic features of diabetes due to recessive, non-syndromic WFS1 mutations. Eur J Endocrinol. 2021;186 (2):163-170. .Li M., Wang S., Xu K., et al. High Prevalence of a Monogenic Cause in Han Chinese Diagnosed With Type 1 Diabetes, Partly Driven by Nonsyndromic Recessive WFS1 Mutations. Diabetes. 2020; 69(1): 121-126.Li M., Wang S., Xu K., et al. High Prevalence of a Monogenic Cause in Han Chinese Diagnosed With Type 1 Diabetes, Partly Driven by Nonsyndromic Recessive WFS1 Mutations. Diabetes. 2020;69(1):121-126.Menon J.C., Singh P., Archana A., et al. High Frequency of Recessive WFS1 Mutations Among Indian Children With Islet Antibody-negative Type 1 Diabetes. J Clin Endocrinol Metab. 2024;20;109(3):e1072-e1082.Menon J.C., Singh P., Archana A., et al. High Frequency of Recessive WFS1 Mutations Among Indian Children With Islet Antibody-negative Type 1 Diabetes. J Clin Endocrinol Metab. 2024;20;109(3):e1072-e1082.Zalloua P.A., Azar S.T., Delépine M., et al. WFS1 mutations are frequent monogenic causes of juvenile-onset diabetes mellitus in Lebanon. Hum Mol Genet. 2008;15;17(24):4012-21.Zalloua P.A., Azar S.T., Delépine M., et al. WFS1 mutations are frequent monogenic causes of juvenile-onset diabetes mellitus in Lebanon. Hum Mol Genet. 2008;15;17(24):4012-21.Rohayem J., Ehlers C., Wiedemann B., et al. Diabetes and neurodegeneration in Wolfram syndrome: a multicenter study of phenotype and genotype. Diabetes Care. 2011;34(7):1503-10.Rohayem J., Ehlers C., Wiedemann B., et al. Diabetes and neurodegeneration in Wolfram syndrome: a multicenter study of phenotype and genotype. Diabetes Care. 2011; 34(7): 1503-1510.De Franco E., Flanagan S.E., Yagi .T, et al. Dominant ER StressInducing WFS1 Mutations Underlie a Genetic Syndrome of Neonatal/Infancy-Onset Diabetes, Congenital Sensorineural Deafness, and Congenital Cataracts. Diabetes. 2017 Jul;66(7):2044-2053.De Franco E., Flanagan S.E., Yagi .T, et al. Dominant ER StressInducing WFS1 Mutations Underlie a Genetic Syndrome of Neonatal/Infancy-Onset Diabetes, Congenital Sensorineural Deafness, and Congenital Cataracts. Diabetes. 2017 Jul;66(7):2044-2053.Kan W., Wang Y., Xue Y., et al A novel heterozygous WFS1 variant of uncertain significance in a patient with early-onset diabetes: a case report. Front Endocrinol. 2026;16:1743282..Kan W., Wang Y., Xue Y., et al A novel heterozygous WFS1 variant of uncertain significance in a patient with early-onset diabetes: a case report. Front Endocrinol. 2026;16:1743282..de Muijnck C., Brink J.B.T., Bergen A.A., et al. Delineating Wolframlike syndrome: A systematic review and discussion of the WFS1-associated disease spectrum. Surv Ophthalmol. 2023;68(4):641-654.de Muijnck C., Brink J.B.T., Bergen A.A., et al. Delineating Wolframlike syndrome: A systematic review and discussion of the WFS1-associated disease spectrum. Surv Ophthalmol. 2023;68(4):641-654.Wu L., Zhang J., Li D., et al. Novel WFS1 variants are associated with different diabetes phenotypes. Front Genet. 2024 Aug 16;15:1433060Wu L., Zhang J., Li D., et al. Novel WFS1 variants are associated with different diabetes phenotypes. Front Genet. 2024 Aug 16;15:1433060

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