Generate QR code
Open Access
Subscription Access
Rare WFS1 Variants in Individuals with a Monogenic Diabetes Phenotype
https://doi.org/10.25557/2073-7998.2026.02.50-54
Abstract
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.
Supporting agencies: This study was supported by the budget project FWNR-2022-0021
About the Authors
D. E. Ivanoshchuk
Federal 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 Sciences
Russian Federation
Russian Federation
10, Prospekt Lavrentyeva, Novosibirsk, 630090, Russian Federation
175/1, Bogatkova st., Novosibirsk, 630004, Russian Federation
A. K. Ovsyannikova
Institute of Internal and Preventive Medicine – branch of Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences
Russian Federation
Russian Federation
175/1, Bogatkova st., Novosibirsk, 630004, Russian Federation
O. D. Rymar
Institute of Internal and Preventive Medicine – branch of Institute of Cytology and Genetics, Siberian Branch of Russian Academy of Sciences
Russian Federation
Russian Federation
175/1, Bogatkova st., Novosibirsk, 630004, Russian Federation
P. S. Orlov
Federal 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 Sciences
Russian Federation
Russian Federation
10, Prospekt Lavrentyeva, Novosibirsk, 630090, Russian Federation
175/1, Bogatkova st., Novosibirsk, 630004, Russian Federation
E. V. Shakhtshneider
Federal 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 Sciences
Russian Federation
Russian Federation
10, Prospekt Lavrentyeva, Novosibirsk, 630090, Russian Federation
175/1, Bogatkova st., Novosibirsk, 630004, Russian Federation
References
1. 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.
2. 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.
3. 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.
4. 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.
5. 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.
6. 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.
7. 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.
8. American Diabetes Association. Standards of medical care in diabetes-2013. Diabetes Care. 2013;(36):11-66.
9. 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.
10. 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.
11. 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. .
12. 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.
13. 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.
14. 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.
15. 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.
16. 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.
17. 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..
18. 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.
19. Wu L., Zhang J., Li D., et al. Novel WFS1 variants are associated with different diabetes phenotypes. Front Genet. 2024 Aug 16;15:1433060
Review
For citations:
Ivanoshchuk D.E., Ovsyannikova A.K., Rymar O.D., Orlov P.S., Shakhtshneider E.V. Rare WFS1 Variants in Individuals with a Monogenic Diabetes Phenotype. Medical Genetics. 2026;25(2):50-54. (In Russ.) https://doi.org/10.25557/2073-7998.2026.02.50-54
Views:
113
JATS XML
Email this article 