Home Hemoglobin A1C can differentiate subjects with GCK mutations among patients suspected to have MODY
Article
Licensed
Unlicensed Requires Authentication

Hemoglobin A1C can differentiate subjects with GCK mutations among patients suspected to have MODY

  • Ceren Yılmaz Uzman EMAIL logo , İbrahim Mert Erbaş ORCID logo , Özlem Giray Bozkaya , Ahu Paketçi , Ahmet Okay Çağlayan , Ayhan Abacı , Melike Ataseven Kulalı , Ece Böber , Arda Kekilli , Tayfun Çinleti , Murat Derya Erçal and Korcan Demir ORCID logo
Published/Copyright: October 5, 2022
Journal of Pediatric Endocrinology and Metabolism
From the journal Journal of Pediatric Endocrinology and Metabolism Volume 35 Issue 12

Abstract

Objectives

The aim of this study is to determine the clinical and molecular characteristics enabling differential diagnosis in a group of Turkish children clinically diagnosed with MODY and identify the cut-off value of HbA1c, which can distinguish patients with GCK variants from young-onset type 1 and type 2 diabetes.

Methods

The study included 49 patients from 48 unrelated families who were admitted between 2018 and 2020 with a clinical diagnosis of MODY. Clinical and laboratory characteristics of the patients at the time of the diagnosis were obtained from hospital records. Variant analysis of ten MODY genes was performed using targeted next-generation sequencing (NGS) panel and the variants were classified according to American Collage of Medical Genetics and Genomics (ACMG) Standards and Guidelines recommendations.

Results

A total of 14 (28%) pathogenic/likely pathogenic variants were detected among 49 patients. 11 variants in GCK and 3 variants in HNF1A genes were found. We identified four novel variants in GCK gene. Using ROC analysis, we found that best cut-off value of HbA1c at the time of diagnosis for predicting the subjects with a GCK variant among patients suspected to have MODY was 6.95% (sensitivity 90%, specificity 86%, AUC 0.89 [95% CI: 0.783–1]). Most of the cases without GCK variant (33/38 [86%]) had an HbA1c value above this cutoff value. We found that among participants suspected of having MODY, family history, HbA1c at the time of diagnosis, and not using insulin therapy were the most differentiating variables of patients with GCK variants.

Conclusions

Family history, HbA1c at the time of diagnosis, and not receiving insulin therapy were found to be the most distinguishing variables of patients with GCK variants among subjects suspected to have MODY.

Keywords: autoantibody; hyperglycemia; metformin; next generation sequencing; repaglinide; risk analysis; sulfonylurea
Corresponding author: Ceren Yilmaz Uzman, Department of Pediatric Genetics, Faculty of Medicine, Dokuz Eylül University, Dr. Behcet Uz Children’s Hospital, İzmir, Turkey, Phone: +90 232 411 36 19, E-mail:

  1. Research funding: None declared.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: Authors state no conflict of interest.

  4. Informed consent: Informed consent was obtained from all individuals included in this study.

  5. Ethical approval: Samples from the patients were obtained in accordance with the Helsinki Declarations. Written informed consent for genetic testing, publication of other medical information, and photographs was obtained from all patients and/or their parents/guardians. This study was approved by the Ethics Committee of Dokuz Eylül University of Medicine (date: December 8, 2021, number:2021/34-4).

References

1. Kleinberger, JW, Pollin, TI. Undiagnosed MODY: time for action. Curr Diabetes Rep 2015;15:458–11. https://doi.org/10.1007/s11892-015-0681-7.Search in Google Scholar PubMed PubMed Central

2. Tatsi, EB, Kanaka-Gantenbein, C, Scorilas, A, Chrousos, GP, Sertedaki, A. Next generation sequencing targeted gene panel in Greek MODY patients increases diagnostic accuracy. Pediatr Diabetes 2020;21:28–39. https://doi.org/10.1111/pedi.12931.Search in Google Scholar PubMed

3. de Santana, LS, Caetano, LA, Costa-Riquetto, AD, Franco, PC, Dotto, RP, Reis, AF, et al.. Targeted sequencing identifies novel variants in common and rare MODY genes. Mol Genet Genomic Med 2019;7:e962. https://doi.org/10.1002/mgg3.962.Search in Google Scholar PubMed PubMed Central

4. Althari, S, Gloyn, AL. When is it MODY? Challenges in the interpretation of sequence variants in MODY genes. Rev Diabet Stud 2015;12:330–48. https://doi.org/10.1900/rds.2015.12.330.Search in Google Scholar

5. Özdemir, TR, Klrblylk, Ö, Dündar, BN, Abacı, A, Kaya, ÖÖ, Çatlı, G, et al.. Targeted next generation sequencing in patients with maturity-onset diabetes of the young (MODY). J Pediatr Endocrinol Metab 2018;31:1295–304. https://doi.org/10.1515/jpem-2018-0184.Search in Google Scholar PubMed

6. Gökşen, D, Yeşilkaya, E, Özen, S, Kor, Y, Eren, E, Korkmaz, Ö, et al.. Molecular diagnosis of monogenic diabetes and their clinical/laboratory features in Turkish children. J Clin Res Pediatr Endocrinol 2021;13:433–8. https://doi.org/10.4274/jcrpe.galenos.2021.2021.0056.Search in Google Scholar PubMed PubMed Central

7. Anik, A, Çatli, G, Abaci, A, Böber, E. Maturity-onset diabetes of the young (MODY): an update. J Pediatr Endocrinol Metab 2015;28:251–63. https://doi.org/10.1515/jpem-2014-0384.Search in Google Scholar PubMed

8. Bonnefond, A, Philippe, J, Durand, E, Dechaume, A, Huyvaert, M, Montagne, L, et al.. Whole-exome sequencing and high throughput genotyping identified KCNJ11 as the thirteenth MODY gene. PLoS One 2012;7:e37423. https://doi.org/10.1371/journal.pone.0037423.Search in Google Scholar PubMed PubMed Central

9. Broome, DT, Pantalone, KM, Kashyap, SR, Philipson, LH. Approach to the patient with MODY-monogenic diabetes. J Clin Endocrinol Metab 2021;106:237–50.https://doi.org/10.1210/clinem/dgaa710.Search in Google Scholar PubMed PubMed Central

10. Richards, S, Aziz, N, Bale, S, Bick, D, Das, S, Gastier-Foster, J, 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;17:405–24. https://doi.org/10.1038/gim.2015.30.Search in Google Scholar PubMed PubMed Central

11. Delvecchio, M, Mozzillo, E, Salzano, G, Iafusco, D, Frontino, G, Patera, PI, et al.. Monogenic diabetes accounts for 6.3% of cases referred to 15 Italian pediatric diabetes centers during 2007 to 2012. J Clin Endocrinol Metab 2017;102:1826–34. https://doi.org/10.1210/jc.2016-2490.Search in Google Scholar PubMed

12. Aykut, A, Karaca, E, Onay, H, Gökşen, D, Çetinkalp, Ş, Eren, E, et al.. Analysis of the GCK gene in 79 MODY type 2 patients: a multicenter Turkish study, mutation profile and description of twenty novel mutations. Gene 2018;641:186–9. https://doi.org/10.1016/j.gene.2017.10.057.Search in Google Scholar PubMed

13. Aǧladioǧlu, SY, Aycan, Z, Çetinkaya, S, Baş, VN, Önder, A, Peltek Kendirci, HN, et al.. Maturity onset diabetes of youth (MODY) in Turkish children: sequence analysis of 11 causative genes by next generation sequencing. J Pediatr Endocrinol Metab 2016;29:487–96.10.1515/jpem-2015-0039Search in Google Scholar PubMed

14. Karaca, E, Onay, H, Cetinkalp, S, Aykut, A, Göksen, D, Ozen, S, et al.. The spectrum of HNF1A gene mutations in patients with MODY 3 phenotype and identification of three novel germline mutations in Turkish Population. Diabetes Metabol Syndr Clin Res Rev 2017;11:S491–6. https://doi.org/10.1016/j.dsx.2017.03.042.Search in Google Scholar PubMed

15. Harries, LW, Sloman, MJ, Sellers, EAC, Hattersley, AT, Ellard, S. Diabetes susceptibility in the Canadian Oji-Cree population is moderated by abnormal mRNA processing of HNF1A G319S transcripts. Diabetes 2008;57:1978–82. https://doi.org/10.2337/db07-1633.Search in Google Scholar

16. Fu, J, Wang, T, Zhai, X, Xiao, X. Primary hepatocellular adenoma due to biallelic HNF1A mutations and its co-occurrence with MODY 3: case-report and review of the literature. Endocrine 2020;67:544–51. https://doi.org/10.1007/s12020-019-02138-x.Search in Google Scholar PubMed PubMed Central

17. Anık, A, Catlı, G, Abacı, A, Sarı, E, Yeşilkaya, E, Korkmaz, HA, et al.. Molecular diagnosis of maturity-onset diabetes of the young (MODY) in Turkish children by using targeted next-generation sequencing. J Pediatr Endocrinol Metab 2015;28:1265–71. https://doi.org/10.1515/jpem-2014-0430.Search in Google Scholar PubMed

18. Altan, M, Anık, A, Işık Bayar, NT, Bozkurt, G, Ünüvar, T, Anık, A. Clinical, laboratory and genetic characteristics of children with GCK-MODY (MODY2): report of four novel variants in GCK gene. Trends Pediatr 2020;1:5–10. https://doi.org/10.5222/tp.2020.58076.Search in Google Scholar

19. Ming-Qiang, Z, Yang-Li, D, Ke, H, Wei, W, Jun-Fen, F, Chao-Chun, Z, et al.. Maturity onset diabetes of the young (MODY) in Chinese children: genes and clinical phenotypes. J Pediatr Endocrinol Metab 2019;32:759–65. https://doi.org/10.1515/jpem-2018-0446.Search in Google Scholar PubMed

20. Xu, A, Lin, Y, Sheng, H, Cheng, J, Mei, H, Ting, TH, et al.. Molecular diagnosis of maturity-onset diabetes of the young in a cohort of Chinese children. Pediatr Diabetes 2020;21:431–40. https://doi.org/10.1111/pedi.129855.Search in Google Scholar

21. Haliloglu, B, Hysenaj, G, Atay, Z, Guran, T, Abalı, S, Turan, S, et al.. GCK gene mutations are a common cause of childhood-onset MODY (maturity-onset diabetes of the young) in Turkey. Clin Endocrinol (Oxf) 2016;85:393–9. https://doi.org/10.1111/cen.13121.Search in Google Scholar PubMed PubMed Central

22. Feigerlová, E, Pruhová, Š, Dittertová, L, Lebl, J, Pinterová, D, Kološtová, K, et al.. Aetiological heterogeneity of asymptomatic hyperglycaemia in children and adolescents. Eur J Pediatr 2006;165:446–52. https://doi.org/10.1007/s00431-006-0106-3.Search in Google Scholar PubMed

23. Codner, E, Rocha, A, Deng, L, Martínez-Aguayo, A, Godoy, C, Mericq, V, et al.. Mild fasting hyperglycemia in children: high rate of glucokinase mutations and some risk of developing type 1 diabetes mellitus. Pediatr Diabetes 2009;10:382–8. https://doi.org/10.1111/j.1399-5448.2009.00499.x.Search in Google Scholar PubMed PubMed Central

24. Lorini, R, Klersy, C, d’Annunzio, G, Massa, O, Minuto, N, Iafusco, D, et al.. Maturity-onset diabetes of the young in children with incidental hyperglycemia: a multicenter Italian study of 172 families. Diabetes Care 2009;32:1864–6. https://doi.org/10.2337/dc08-2018.Search in Google Scholar PubMed PubMed Central

25. Gloyn, AL, van de Bunt, M, Stratton, IM, Lonie, L, Tucker, L, Ellard, S, et al.. Prevalence of GCK mutations in individuals screened for fasting hyperglycaemia. Diabetologia 2009;52:172–4. https://doi.org/10.1007/s00125-008-1188-4.Search in Google Scholar PubMed

26. Thanabalasingham, G, Pal, A, Selwood, MP, Dudley, C, Fisher, K, Bingley, PJ, et al.. Systematic assessment of etiology in adults with a clinical diagnosis of young-onset type 2 diabetes is a successful strategy for identifying maturity-onset diabetes of the young. Diabetes Care 2012;35:1206–12. https://doi.org/10.2337/dc11-1243.Search in Google Scholar PubMed PubMed Central

27. Chakera, AJ, Steele, AM, Gloyn, AL, Shepherd, MH, Shields, B, Ellard, S, et al.. Recognition and management of individuals with hyperglycemia because of a heterozygous glucokinase mutation. Diabetes Care 2015;38:1383–92. https://doi.org/10.2337/dc14-2769.Search in Google Scholar PubMed

28. Martin, D, Bellanné-Chantelot, C, Deschamps, I, Froguel, P, Robert, JJ, Velho, G. Long-term follow-up of oral glucose tolerance test-derived glucose tolerance and insulin secretion and insulin sensitivity indexes in subjects with glucokinase mutations (MODY2). Diabetes Care 2008;31:1321–3. https://doi.org/10.2337/dc07-2017.Search in Google Scholar PubMed PubMed Central

29. Pearson, ER, Velho, G, Clark, P, Stride, A, Shepherd, M, Frayling, TM, et al.. beta-cell genes and diabetes: quantitative and qualitative differences in the pathophysiology of hepatic nuclear factor-1alpha and glucokinase mutations. Diabetes 2001;50:S101–7. https://doi.org/10.2337/diabetes.50.2007.s101.Search in Google Scholar PubMed

30. Urakami, T. Maturity-onset diabetes of the young (MODY): current perspectives on diagnosis and treatment. Diabetes Metab Syndr Obes 2019;12:1047–56. https://doi.org/10.2147/dmso.s179793.Search in Google Scholar

31. Steele, AM, Wensley, KJ, Ellard, S, Murphy, R, Shepherd, M, Colclough, K, et al.. Use of HbA1c in the identification of patients with hyperglycaemia caused by a glucokinase mutation: observational case control studies. PLoS One 2013;8:e65326. https://doi.org/10.1371/journal.pone.0065326.Search in Google Scholar PubMed PubMed Central

32. Shields, BM, McDonald, TJ, Ellard, S, Campbell, MJ, Hyde, C, Hattersley, AT. The development and validation of a clinical prediction model to determine the probability of MODY in patients with young-onset diabetes. Diabetologia 2012;55:1265–72. https://doi.org/10.1007/s00125-011-2418-8.Search in Google Scholar PubMed PubMed Central

33. Hulín, J, Škopková, M, Valkovıčová, T, Mıkulajová, S, Rosoľanková, M, Papcun, P, et al.. Clinical implications of the glucokinase impaired function -GCK-MODY today. Physiol Res 2020;69:995–1011. https://doi.org/10.33549/physiolres.934487.Search in Google Scholar PubMed PubMed Central

34. Radin, MS. Pitfalls in hemoglobin A1c measurement: when results may be misleading. J Gen Intern Med 2014;29:388–94. https://doi.org/10.1007/s11606-013-2595-x.Search in Google Scholar PubMed PubMed Central

35. Hattersley, A, Bruining, J, Shield, J, Njolstad, P, Donaghue, K. International Society for Pediatric and Adolescent Diabetes. ISPAD Clinical Practice Consensus Guidelines 2006-2007. The diagnosis and management of monogenic diabetes in children. Pediatr Diabetes 2006;7:352–60. https://doi.org/10.1111/j.1399-5448.2006.00217.x.Search in Google Scholar PubMed

36. Tatsi, C, Kanaka-Gantenbein, C, Vazeou-Gerassimidi, A, Chrysis, D, Delis, D, Tentolouris, N, et al.. The spectrum of HNF1A gene mutations in Greek patients with MODY3: relative frequency and identification of seven novel germline mutations. Pediatr Diabetes 2013;14:526–34. https://doi.org/10.1111/pedi.12032.Search in Google Scholar PubMed

37. Çubuk, H, Yalçın Çapan, Ö. A review of functional characterization of single amino acid change mutations in HNF transcription factors in MODY pathogenesis. Protein J 2021;40:348–60. https://doi.org/10.1007/s10930-021-09991-8.Search in Google Scholar PubMed

38. Hegele, RA, Cao, H, Harris, SB, Hanley, AJ, Zinman, B. The hepatic nuclear factor-1alpha G319S variant is associated with early-onset type 2 diabetes in Canadian Oji-Cree. J Clin Endocrinol Metab 1999;84:1077–82. https://doi.org/10.1210/jcem.84.3.5528.Search in Google Scholar PubMed

39. Colclough, K, Bellanne-Chantelot, C, Saint-Martin, C, Flanagan, SE, Ellard, S. Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha and 4 alpha in maturity-onset diabetes of the young and hyperinsulinemic hypoglycemia. Hum Mutat 2013;34:669–85. https://doi.org/10.1002/humu.22279.Search in Google Scholar PubMed

40. Harries, LW, Ellard, S, Stride, A, Morgan, NG, Hattersley, AT. Isomers of the TCF1 gene encoding hepatocyte nuclear factor-1 alpha show differential expression in the pancreas and define the relationship between mutation position and clinical phenotype in monogenic diabetes. Hum Mol Genet 2006;15:2216–24. https://doi.org/10.1093/hmg/ddl147.Search in Google Scholar PubMed

41. Pruhova, S, Dusatkova, P, Neumann, D, Hollay, E, Cinek, O, Lebl, J, et al.. Two cases of diabetic ketoacidosis in HNF1A-MODY linked to severe dehydration: is it time to change the diagnostic criteria for MODY? Diabetes Care 2013;36:2573–4. https://doi.org/10.2337/dc13-0058.Search in Google Scholar PubMed PubMed Central

42. Juszczak, A, Pryse, R, Schuman, A, Owen, KR. When to consider a diagnosis of MODY at the presentation of diabetes: aetiology matters for correct management. Br J Gen Pract 2016;66:e457–9. https://doi.org/10.3399/bjgp16x685537.Search in Google Scholar PubMed PubMed Central

43. Naylor, R, Philipson, LH. Who should have genetic testing for maturity-onset diabetes of the young? Clin Endocrinol (Oxf) 2011;75:422–6. https://doi.org/10.1111/j.1365-2265.2011.04049.x.Search in Google Scholar PubMed

44. Ellard, S, Lango Allen, H, de Franco, E, Flanagan, SE, Hysenaj, G, Colclough, K, et al.. Improved genetic testing for monogenic diabetes using targeted next-generation sequencing. Diabetologia 2013;56:1958–63. https://doi.org/10.1007/s00125-013-2962-5.Search in Google Scholar PubMed PubMed Central

45. Ellard, S, Bellanné-Chantelot, C, Hattersley, AT, European Molecular Genetics Quality Network (EMQN) MODY group. Best practice guidelines for the molecular genetic diagnosis of maturity-onset diabetes of the young. Diabetologia 2008;51:546–53. https://doi.org/10.1007/s00125-008-0942-y.Search in Google Scholar PubMed PubMed Central

46. Pezzilli, S, Ludovico, O, Biagini, T, Mercuri, L, Alberico, F, Lauricella E, et al.. Insights from molecular characterization of adult patients of families with multigenerational diabetes. Diabetes 2018;67:137–45. https://doi.org/10.2337/db17-0867.Search in Google Scholar PubMed

47. Garin, I, Rica, I, Estalella, I, Oyarzabal, M, Rodríguez-Rigual, M, San Pedro, JI, et al.. Haploinsufficiency at GCK gene is not a frequent event in MODY2 patients. Clin Endocrinol (Oxf) 2008;68:873–8. https://doi.org/10.1111/j.1365-2265.2008.03214.x.Search in Google Scholar PubMed

48. Bellanné -Chantelot, C, Clauin, S, Chauveau, D, Collin P, Daumont M, Douillard C, et al.. Large genomic rearrangements in the hepatocyte nuclear factor-1beta (TCF2) gene are the most frequent cause of maturity-onset diabetes of the young type 5. Diabetes 2005;54:3126–32. https://doi.org/10.2337/diabetes.54.11.3126.Search in Google Scholar PubMed

Received: 2022-08-02
Accepted: 2022-09-13
Published Online: 2022-10-05
Published in Print: 2022-12-16

© 2022 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Review Article
  3. The efficacy and safety of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 agonists in pediatric patients with type 2 diabetes: a systematic review
  4. Original Articles
  5. Triple burden of malnutrition and role of anaemia in the development of complications associated with type 1 diabetes in Indian children and youth
  6. Effect of obesity and excessive body fat on glycaemic control in paediatric type 1 diabetes
  7. Role of pan immune inflammatory value in the evaluation of hepatosteatosis in children and adolescents with obesity
  8. Secular trends of birth weight and its associations with obesity and hypertension among Southern Chinese children and adolescents
  9. Insights into the implication of obesity in hypogonadism among adolescent boys
  10. The association between plasma carnitines and duration of diabetic ketoacidosis treatment in children with type 1 diabetes
  11. Cathelicidin as a marker for subclinical cardiac changes and microvascular complications in children and adolescents with type 1 diabetes
  12. Developing a risk assessment tool for identifying individuals at high risk for developing insulin resistance in European adolescents: the HELENA-IR score
  13. Hemoglobin A1C can differentiate subjects with GCK mutations among patients suspected to have MODY
  14. Perceptions and use of complementary and alternative medicine in patients with precocious puberty
  15. Case Reports
  16. Infection with SARS-CoV-2 may alter the half-life of desmopressin (DDAVP) in patients with central diabetes insipidus
  17. Heterozygous CDC73 mutation causing hyperparathyroidism in children and adolescents: a report of 2 cases
  18. Wolfram syndrome in a young woman with associated hypergonadotropic hypogonadism – A case report
  19. Continuous glucose monitoring in an infant with panhypopituitarism having hypoglycemia on growth hormone therapy
  20. Severe consumptive hypothyroidism in hepatic hemangioendothelioma
  21. Efficacy of aromatase inhibitor therapy in a case with large cell calcifying Sertoli cell tumour-associated prepubertal gynaecomastia
https://doi.org/10.1515/jpem-2022-0381
Keywords for this article
autoantibody; hyperglycemia; metformin; next generation sequencing; repaglinide; risk analysis; sulfonylurea

Articles in the same Issue

  1. Frontmatter
  2. Review Article
  3. The efficacy and safety of dipeptidyl peptidase-4 inhibitors and glucagon-like peptide-1 agonists in pediatric patients with type 2 diabetes: a systematic review
  4. Original Articles
  5. Triple burden of malnutrition and role of anaemia in the development of complications associated with type 1 diabetes in Indian children and youth
  6. Effect of obesity and excessive body fat on glycaemic control in paediatric type 1 diabetes
  7. Role of pan immune inflammatory value in the evaluation of hepatosteatosis in children and adolescents with obesity
  8. Secular trends of birth weight and its associations with obesity and hypertension among Southern Chinese children and adolescents
  9. Insights into the implication of obesity in hypogonadism among adolescent boys
  10. The association between plasma carnitines and duration of diabetic ketoacidosis treatment in children with type 1 diabetes
  11. Cathelicidin as a marker for subclinical cardiac changes and microvascular complications in children and adolescents with type 1 diabetes
  12. Developing a risk assessment tool for identifying individuals at high risk for developing insulin resistance in European adolescents: the HELENA-IR score
  13. Hemoglobin A1C can differentiate subjects with GCK mutations among patients suspected to have MODY
  14. Perceptions and use of complementary and alternative medicine in patients with precocious puberty
  15. Case Reports
  16. Infection with SARS-CoV-2 may alter the half-life of desmopressin (DDAVP) in patients with central diabetes insipidus
  17. Heterozygous CDC73 mutation causing hyperparathyroidism in children and adolescents: a report of 2 cases
  18. Wolfram syndrome in a young woman with associated hypergonadotropic hypogonadism – A case report
  19. Continuous glucose monitoring in an infant with panhypopituitarism having hypoglycemia on growth hormone therapy
  20. Severe consumptive hypothyroidism in hepatic hemangioendothelioma
  21. Efficacy of aromatase inhibitor therapy in a case with large cell calcifying Sertoli cell tumour-associated prepubertal gynaecomastia
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 9.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/jpem-2022-0381/html
Scroll to top button