Clinical Genetic Database as a Tool for Comprehensive Analysis of Orphan Disease Using Wilson's Disease as an Example

Aim: to conduct a comprehensive analysis of the clinical-genetic database of patients with Wilson’s disease and to evaluate the possibilities of using it as a tool for epidemiological and clinical research.

Materials and methods. The study is based on data from 296 patients diagnosed with Wilson’s disease (WD), included in the clinical-genetic database for the period 2015–2025. The study involved a comprehensive assessment of results of clinical examinations of patients, including initial diagnosis and monitoring of their condition; laboratory test data, including molecular-genetic studies (performed using next generation sequencing and polymerase chain reaction); results of instrumental examinations.

Results. The analysis of the clinical genetic database of patients with Wilson’s disease included data on 296 patients: 120 males and 176 females. The age of the study participants ranged from 14 to 67 years, with a mean age of 30.0 ± 6.5 years. Among the examined patients, 281 (94.94 %) individuals reside in the Russian Federation.

Analysis of the distribution of patients by clinical forms of the disease revealed the following: abdominal form of WD was diagnosed in 140 (47.29 %) patients; neurological form — in 18 (6.09 %); mixed form — in 99 (33.45 %); asymptomatic form — in 39 (13.17 %) patients.

When studying the characteristics of disease onset, it was found that 67 (22.63 %) patients had no pronounced clinical manifestations at the time of diagnosis. Among them, 17 patients (25.37 % of those with asymptomatic onset) were diagnosed through family screening.

Molecular-genetic testing of the ATP7B gene was performed in 146 patients. Among the identified pathogenic variants, the most common was c.3207C>A (p.His1069Gln), detected in 114 (78.08 %) patients. The majority of patients (72.5 %) were compound heterozygotes, while rare variants of the ATP7B gene were found in 16.15 % of cases.

Additionally, an analysis of course in WD patients who had COVID-19 was conducted. The results showed that 41.1 % experienced worsening of neurological symptoms. Furthermore, 9.8 % of patients with initially asymptomatic WD developed the first clinical manifestations of the disease after COVID-19 infection.

Conclusions. The developed clinical-genetic database is an effective tool for studying WD, providing an informational basis for further epidemiological, clinical, and molecular genetic research.

1. Nguengang Wakap S., Lambert D.M., Olry A., Rodwell C., Gueydan C., Lanneau V., et al. Estimating cumulative point prevalence of rare diseases: Analysis of the Orphanet database. Eur J Hum Genet. 2020;28(2):165–73. DOI: 10.1038/s41431-019-0508-0

2. Félix T.M., de Oliveira B.M., Artifon M., Carvalho I., Bernardi F.A., Schwartz I.V.D, et al.; RARAS Network group. Epidemiology of rare diseases in Brazil: Protocol of the Brazilian Rare Diseases Network (RARAS-BRDN). Orphanet J Rare Dis. 2022;17(1):84. DOI: 10.1186/s13023-022-02254-4

3. Graefe A.S.L., Hübner M.R., Rehburg F., Sander S., Klopfenstein S.A.I., Alkarkoukly S., et al. An ontology-based rare disease common data model harmonising international registries, FHIR, and Phenopackets. Sci Data. 2025;12(1):234. DOI: 10.1038/s41597-025-04558-z

4. Volkova N.S., Aksu E. Rare (orphan) diseases: Legal regulation abroad. Journal of Foreign Legislation and Comparative Law. 2018;4:154–60. (In Russ.). DOI: 10.12737/art.2018.4.20

5. Gayduk A.I., Vlasov Ya.V., Zakharova E.Yu. Current problems of providing medical care for patients with orphan diseases in the Russian Federation. Medical genetics. 2020;19(11):13–20. (In Russ.). DOI: 10.25557/2073-7998.2020.11.13-20

6. Poujois A., Woimant F. Wilson’s disease: A 2017 update. Clin Res Hepatol Gastroenterol. 2018;42(6):512–20. DOI: 10.1016/j.clinre.2018.03.007

7. Trocello J.M., Broussolle E., Girardot-Tinant N., Pelosse M., Lachaux A., Lloyd C., et al. Wilson’s disease, 100 years later…. Rev Neurol (Paris). 2013;169(12):936–43. DOI: 10.1016/j.neurol.2013.05.002

8. Sandahl T.D., Laursen T.L., Munk D.E., Vilstrup H., Weiss K.H., Ott P. The prevalence of Wilson’s disease: An update. Hepatology. 2020;71(2):722–32. DOI: 10.1002/hep.30911

9. Członkowska A., Niewada M., Litwin T., Kraiński Ł., Skowrońska M., Piechal A., et al. Seven decades of clinical experience with Wilson’s disease: Report from the National Reference Centre in Poland. Eur J Neurol. 2024;31(11):e15646. DOI: 10.1111/ene.15646

10. Garbuz M., Ovchinnikova E., Ovchinnikova A., Vinokurova V., Aristarkhova Y., Kuziakova O., et al. Spectrum of pathogenic variants of the ATP7B gene and genotype-phenotype correlation in Eastern Eurasian patient cohorts with Wilson’s disease. Biomedicines. 2024;12(12):2833. DOI: 10.3390/biomedicines12122833

11. Xiao Q.Q., Wang Z.X., Fan J.G. Factors influencing the clinical phenotype of hepatolenticular degeneration. Zhonghua Gan Zang Bing Za Zhi. 2023;31(2):207–11. (In Chinese). DOI: 10.3760/cma.j.cn501113-20211124-00579

12. Daniel-Robin T., Kumar P., Benichou B., Combal J.P. Characteristics of patients with Wilson disease in the United States: An insurance claims database study. World J Hepatol. 2024;16(5):791–9. DOI: 10.4254/wjh.v16.i5.791

13. Bezin J., Duong M., Lassalle R., Droz C., Pariente A., Blin P., et al. The national healthcare system claims databases in France, SNIIRAM and EGB: Powerful tools for pharmacoepidemiology. Pharmacoepidemiol Drug Saf. 2017;26(8):954–62. DOI: 10.1002/pds.4233

14. Patel A.H., Ghattu M., Mazzaferro N., Chen A., Catalano K., Minacapelli C.D., et al. Demographics and outcomes related to Wilson’s disease patients: A Nationwide Inpatient Cohort Study. Cureus. 2023;15(9):e44714. DOI: 10.7759/cureus.44714

15. Ryzhkova O.P., Kardymon O.L., Prohorchuk E.B., Konovalov F.A., Maslennikov A.B., Stepanov V.A., et al. Guidelines for the interpretation of massive parallel sequencing variants (update 2018, v2). Medical genetics. 2019;18(2):3–23. (In Russ.). DOI: 10.25557/2073-7998.2019.02.3-23

16. Richards S., Aziz N., Bale S., Bick D., Das S., Gastier-Foster J., et al.; ACMG Laboratory Quality Assurance Committee. 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(5):405–24. DOI: 10.1038/gim.2015.30

17. Ministry of Health of the Russian Federation. Clinical guidelines. Copper metabolism disorders (Wilson’s disease). 2024. (In Russ.).

18. Balashova M.S., Tuluzanovskaya I.G., Glotov O.S., Glotov A.S., Barbitoff Y.A., Fedyakov M.A., et al. The spectrum of pathogenic variants of the ATP7B gene in Wilson disease in the Russian Federation. J Trace Elem Med Biol. 2020;59:126420. DOI: 10.1016/j.jtemb.2019.126420

19. Tuluzanovskaya I.G., Balashova M.S., Zhuchenko N.A., Glotov O.S., Glotov A.S., Filimonov M.I., et al. Mutations in the HFE gene causing hereditary hemochromatosis in patients with Wilson disease. Experimental and Clinical Gastroenterology. 2018;159(11):33–7. (In Russ.). DOI: 10.31146/1682-8658-ecg-159-11-33-37

20. Balashova M.S., Soloveva O.V., Tuluzanovskaya I.G., Filimonov M.I., et al. Observation of a combination of Wilson’s disease (WD), hereditary fructose intolerance and chronic hepatitis C (hCG). Proceedings of the XXII annual Russian Congress “Hepatology Today”. Moscow, 2017;26. (In Russ.).

21. Belousova O.B., Okishev D.N., Ignatova T.M., Balashova M.S., Boulygina E.S. Hereditary multiple cerebral cavernous malformations associated with Wilson disease and multiple lipomatosis: Case report. J World Neurosurg, 2017;105:1034.e1–6. DOI: 10.1016/j.wneu.2017.06.002

22. Tuluzanovskaya I.G., Burenchev S.D., Rozina T.P., Starostina E.E., Subbotina T.I., Chebelyaev I.Yu., et al. The debut of Wilson disease during COVID-19: A clinical case study. Infectious Diseases. 2024;22(4):127–30. (In Russ.). DOI: 10.20953/1729-9225-2024-4-127-130

23. Wahler S., Weiss K.H. Hospitalization patterns of Wilson disease in Germany in comparison with US experience. Hepatology. 2020;72(Suppl 1):865–6.

24. Couchonnal E., Bouchard S., Sandahl T.D., Pagan C., Lion-François L., Guillaud O., et al. ATP7B variant spectrum in a French pediatric Wilson disease cohort. Eur J Med Genet. 2021;64(10):104305. DOI: 10.1016/j.ejmg.2021.104305

25. Hromić-Jahjefendić A., Barh D., Ramalho Pinto C.H., Gabriel Rodrigues Gomes L., Picanço Machado J.L., Afolabi O.O., et al. Associations and disease-disease interactions of COVID-19 with congenital and genetic disorders: A comprehensive review. Viruses. 2022;14(5):910. DOI: 10.3390/v14050910