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Study of the frequency and clinical features of maturity-onset diabetes in the young in the pediatric and adolescent diabetes population in Iran

  • Daniel Zamanfar ORCID logo , Fatemeh Ferdosipour ORCID logo , Pirooz Ebrahimi ORCID logo , Mohamad Moghadam ORCID logo , Mahsa M. Amoli ORCID logo , Mojgan Asadi ORCID logo and Mahila Monajati ORCID logo EMAIL logo
Published/Copyright: September 15, 2022
Journal of Pediatric Endocrinology and Metabolism
From the journal Journal of Pediatric Endocrinology and Metabolism Volume 35 Issue 10

Abstract

Objectives

Maturity-onset diabetes of the young (MODY), an autosomal dominant disease, is frequently misdiagnosed as type 1 or 2 diabetes. Molecular diagnosis is essential to distinguish them. This study was done to investigate the prevalence of MODY subtypes and patients’ clinical characteristics.

Methods

A total of 43 out of 230 individuals with diabetes were selected based on the age of diagnosis >6 months, family history of diabetes, absence of marked obesity, and measurable C-peptide. Next-generation and direct SANGER sequencing was performed to screen MODY-related mutations. The variants were interpreted using the Genome Aggregation Database (genomAD), Clinical Variation (ClinVar), and pathogenicity prediction tools.

Results

There were 23 males (53.5%), and the mean age at diabetes diagnosis was 6.7 ± 3.6 years. Sixteen heterozygote single nucleotide variations (SNVs) from 14 patients (14/230, 6%) were detected, frequently GCK (37.5%) and BLK (18.7%). Two novel variants were identified in HNF4A and ABCC8. Half of the detected variants were categorized as likely pathogenic. Most prediction tools predicted Ser28Cys in HNF4A as benign and Tyr123Phe in ABCC8 as a pathogenic SNV. Six cases (42.8%) with positive MODY SNVs had islet autoantibodies. At diagnosis, age, HbA1c, and C-peptide level were similar between SNV-positive and negative patients.

Conclusions

This is the first study investigating 14 variants of MODY in Iran. The results recommend genetic screening for MODY in individuals with unusual type 1 or 2 diabetes even without family history. Treatment modifies depending on the type of patients’ MODY and is associated with the quality of life.

Keywords: MODY subtypes; monogenic diabetes; next-generation sequencing; pediatric diabetes
Corresponding author: Mahila Monajati, Department of Internal Medicine, Golestan University of Medical Sciences, Gorgan, Iran, Fax/Phone: 00981732261162, E-mail:

Funding source: Research Vice Chancellor of Mazandaran University of Medical Sciences

Acknowledgments

We sincerely thank all patients, and their families. We appreciate the assistance of the Clinical Research and Development Unit of Bu-Ali Sina Hospital, Mazandaran University of Medical Sciences, Sari, Iran.

  1. Research funding: The source of financial grants was supported by Research Vice Chancellor of Mazandaran University of Medical Sciences.

  2. Author contributions: Zamanfar D conceptualized, designed the study, and analyzed the data; Ferdosipour F collected the data. Amoli M.M and Asadi M collected and analyzed the genetic data. Ebrahimi M and Moghdam M assessed the pathogenicity of variants. Zamanfar D and Monajati M drafted the initial manuscript. All authors have accepted responsibility for the entire content of this submitted 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: The study was approved by the Ethics Committee of the Mazandaran University of Medical Science (approval ID: IR.MAZUMS.IMAMHOSPITAL.REC.1396.1177). Data were collected anonymously. All the principles, outlined in the Helsinki Declaration, were followed during the investigation.

References

1. Hattersley, AT, Greeley, SA, Polak, M, Rubio-Cabezas, O, Njølstad, PR, Mlynarski, W, et al.. ISPAD clinical practice consensus guidelines 2018: the diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabetes 2018;19:47–63. https://doi.org/10.1111/pedi.12772.Search in Google Scholar PubMed

2. Fajans, SS, Bell, GI. MODY: history, genetics, pathophysiology, and clinical decision making. Diabetes Care 2011;34:1878–84. https://doi.org/10.2337/dc11-0035.Search in Google Scholar PubMed PubMed Central

3. Rubio-Cabezas, O, Hattersley, AT, Njølstad, PR, Mlynarski, W, Ellard, S, White, N, et al.. The diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabetes 2014;15:47–64. https://doi.org/10.1111/pedi.12192.Search in Google Scholar PubMed

4. Aarthy, R, Aston-Mourney, K, Mikocka-Walus, A, Radha, V, Amutha, A, Anjana, RM, et al.. Clinical features, complications and treatment of rarer forms of maturity-onset diabetes of the young (MODY)-A review. J Diabet Complicat 2021;35:107640. https://doi.org/10.1016/j.jdiacomp.2020.107640.Search in Google Scholar PubMed

5. 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 2016;85:393–9. https://doi.org/10.1111/cen.13121.Search in Google Scholar PubMed PubMed Central

6. Shields, BM, Shepherd, M, Hudson, M, McDonald, TJ, Colclough, K, Peters, J, et al.. Population-based assessment of a biomarker-based screening pathway to aid diagnosis of monogenic diabetes in young-onset patients. Diabetes Care 2017;40:1017–25. https://doi.org/10.2337/dc17-0224.Search in Google Scholar PubMed PubMed Central

7. Johansson, BB, Irgens, HU, Molnes, J, Sztromwasser, P, Aukrust, I, Juliusson, PB, et al.. Targeted next-generation sequencing reveals MODY in up to 6.5% of antibody-negative diabetes cases listed in the Norwegian Childhood Diabetes Registry. Diabetol 2017;60:625–35. https://doi.org/10.1007/s00125-016-4167-1.Search in Google Scholar PubMed

8. 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

9. Vaxillaire, M, Bonnefond, A, Liatis, S, Hachmi, LBS, Jotic, A, Boissel, M, et al.. Monogenic diabetes characteristics in a transnational multicenter study from Mediterranean countries. Diabetes Res Clin Pract 2021;171:108553. https://doi.org/10.1016/j.diabres.2020.108553.Search in Google Scholar PubMed

10. Taghavi, SM, Fatemi, SS, Rafatpanah, H, Ganjali, R, Tavakolafshari, J, Valizadeh, N. Mutations in the coding regions of the hepatocyte nuclear factor 4 alpha in Iranian families with maturity onset diabetes of the young. Cardiovasc Diabetol 2009;8:63. https://doi.org/10.1186/1475-2840-8-63.Search in Google Scholar PubMed PubMed Central

11. Moghbeli, M, Naghibzadeh, B, Ghahraman, M, Fatemi, S, Taghavi, M, Vakili, R, et al.. Mutations in HNF1A gene are not a common cause of familial young-onset diabetes in Iran. Indian J Clin Biochem 2018;33:91–5. https://doi.org/10.1007/s12291-017-0648-3.Search in Google Scholar PubMed PubMed Central

12. Javadi, M, Rafatpanah, H, Taghavi, SM, Tavakolafshari, J, Ganjali, R, Valizadeh, N, et al.. Analysis of the glucokinase gene in Iranian families with maturity onset diabetes of the young. J Diabetes Mellitus 2013;3:192–8. https://doi.org/10.4236/jdm.2013.34029.Search in Google Scholar

13. Mohammadi, A, Eskandari, A, Sarmadi, A, Rahimi, M, Iraj, B, Hashemipour, M, et al.. Genetic study of hepatocyte nuclear factor 1 alpha variants in development of early-onset diabetes type 2 and maturity-onset diabetes of the young 3 in Iran. Adv Biomed Res 2019;8:55–63. https://doi.org/10.4103/abr.abr_54_19.Search in Google Scholar PubMed PubMed Central

14. Sarmadi, A, Mohammadi, A, Tabatabaei, F, Nouri, Z, Chaleshtori, MH, Tabatabaiefar, MA. Molecular genetic study in a cohort of Iranian families suspected to maturity-onset diabetes of the young, reveals a recurrent mutation and a high-risk variant in the CEL gene. Adv Biomed Res 2020;9:25–31. https://doi.org/10.4103/abr.abr_18_20.Search in Google Scholar PubMed PubMed Central

15. Karaoglan, M, Nacarkahya, G. Clinical and laboratory clues of maturity-onset diabetes of the young and determination of association with molecular diagnosis. J Diabetes 2021;13:154–63. https://doi.org/10.1111/1753-0407.13097.Search in Google Scholar PubMed

16. Park, SS, Jang, SS, Ahn, CH, Kim, JH, Jung, HS, Cho, YM, et al.. Identifying pathogenic variants of monogenic diabetes using targeted panel sequencing in an east asian population. J Clin Endocrinol Metab 2019;104:4188–98. https://doi.org/10.1210/jc.2018-02397.Search in Google Scholar PubMed

17. Lambert, AP, Ellard, S, Allen, LI, Gallen, IW, Gillespie, KM, Bingley, PJ, et al.. Identifying hepatic nuclear factor 1α mutations in children and young adults with a clinical diagnosis of type 1 diabetes. Diabetes Care 2003;26:333–7. https://doi.org/10.2337/diacare.26.2.333.Search in Google Scholar PubMed

18. Kleinberger, JW, Copeland, KC, Gandica, RG, Haymond, MW, Levitsky, LL, Linder, B, et al.. Monogenic diabetes in overweight and obese youth diagnosed with type 2 diabetes: the TODAY clinical trial. Genet Med 2018;20:583–90. https://doi.org/10.1038/gim.2017.150.Search in Google Scholar PubMed PubMed Central

19. Shields, B, McDonald, TJ, Ellard, S, Campbell, M, 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. Diabetol 2012;55:1265–72. https://doi.org/10.1007/s00125-011-2418-8.Search in Google Scholar PubMed PubMed Central

20. Mayer-Davis, EJ, Kahkoska, AR, Jefferies, C, Dabelea, D, Balde, N, Gong, CX, et al.. ISPAD clinical practice consensus guidelines 2018: definition, epidemiology, and classification of diabetes in children and adolescents. Pediatr Diabetes 2018;19:7–19. https://doi.org/10.1111/pedi.12773.Search in Google Scholar PubMed PubMed Central

21. Sajjadi-Jazi, SM, Soltani, A, Enayati, S, Kakavand Hamidi, A, Amoli, MM. Autoimmune polyglandular syndrome type 1: a case report. BMC Med Genet 2019;20:143. https://doi.org/10.1186/s12881-019-0870-3.Search in Google Scholar PubMed PubMed Central

22. 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;17:405–23. https://doi.org/10.1038/gim.2015.30.Search in Google Scholar PubMed PubMed Central

23. Leong, IU, Stuckey, A, Lai, D, Skinner, JR, Love, DR. Assessment of the predictive accuracy of five in silico prediction tools, alone or in combination, and two metaservers to classify long QT syndrome gene mutations. BMC Med Genet 2015;16:34. https://doi.org/10.1186/s12881-015-0176-z.Search in Google Scholar PubMed PubMed Central

24. Kleinberger, JW. Pollin, TI. Undiagnosed MODY: time for action. Curr Diabetes Rep 2015;15:110. https://doi.org/10.1007/s11892-015-0681-7.Search in Google Scholar PubMed PubMed Central

25. Gardner, DS, Tai, ES. Clinical features and treatment of maturity onset diabetes of the young (MODY). Diabetes Metab Syndr Obes 2012;5:101. https://doi.org/10.2147/dmso.s23353.Search in Google Scholar

26. Pearson, E, Pruhova, S, Tack, C, Johansen, A, Castleden, H, Lumb, P, et al.. Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4α mutations in a large European collection. Diabetol 2005;48:878–85. https://doi.org/10.1007/s00125-005-1738-y.Search in Google Scholar PubMed

27. Yalçıntepe, S, Çömlek, FÖ, Gürkan, H, Demir, S, Atlı, Eİ, Atlı, E, et al.. The application of next generation sequencing maturity onset diabetes of the young gene panel in Turkish patients from trakya region. J Clin Res Pediatr Endocrinol 2021;13:320–31. https://doi.org/10.4274/jcrpe.galenos.2021.2020.0285.Search in Google Scholar PubMed PubMed Central

28. Yamagata, K, Oda, N, Kaisaki, PJ, Menzel, S, Furuta, H, Vaxillaire, M, et al.. Mutations in the hepatocyte nuclear factor-1α gene in maturity-onset diabetes of the young (MODY3). Nat 1996;384:455–8. https://doi.org/10.1038/384455a0.Search in Google Scholar PubMed

29. Carette, C, Dubois-Laforgue, D, Saint-Martin, C, Clauin, S, Beaufils, S, Larger, E, et al.. Familial young-onset forms of diabetes related to HNF4A and rare HNF1A molecular aetiologies. Diabet Med 2010;27:1454–8. https://doi.org/10.1111/j.1464-5491.2010.03115.x.Search in Google Scholar PubMed

30. Ellard, S, Bellanné-Chantelot, C, Hattersley, A. Best practice guidelines for the molecular genetic diagnosis of maturity-onset diabetes of the young. Diabetol 2008;51:546–53. https://doi.org/10.1007/s00125-008-0942-y.Search in Google Scholar PubMed PubMed Central

31. Borowiec, M, Liew, CW, Thompson, R, Boonyasrisawat, W, Hu, J, Mlynarski, WM, et al.. Mutations at the BLK locus linked to maturity onset diabetes of the young and β-cell dysfunction. Proc Natl Acad Sci USA 2009;106:14460–5. https://doi.org/10.1073/pnas.0906474106.Search in Google Scholar PubMed PubMed Central

32. Bonnefond, A, Yengo, L, Philippe, J, Dechaume, A, Ezzidi, I, Vaillant, E, et al.. Reassessment of the putative role of BLK-p. A71T loss-of-function mutation in MODY and type 2 diabetes. Diabetol 2013;56:492–6. https://doi.org/10.1007/s00125-012-2794-8.Search in Google Scholar PubMed

33. Abouelhoda, M, Faquih, T, El-Kalioby, M, Alkuraya, FS. Revisiting the morbid genome of Mendelian disorders. Genome Biol 2016;17:1–7. https://doi.org/10.1186/s13059-016-1102-1.Search in Google Scholar PubMed PubMed Central

34. Ellard, S, Colclough, K, Patel, KA, Hattersley, AT. Prediction algorithms: pitfalls in interpreting genetic variants of autosomal dominant monogenic diabetes. J Clin Invest 2020;130:14–6. https://doi.org/10.1172/jci133516.Search in Google Scholar PubMed PubMed Central

35. Deng, M, Xiao, X, Zhou, L, Wang, T. First case report of maturity-onset diabetes of the young type 4 pedigree in a Chinese family. Front Endocrinol 2019;10:406. https://doi.org/10.3389/fendo.2019.00406.Search in Google Scholar PubMed PubMed Central

36. Gragnoli, C, Stanojevic, V, Gorini, A, Von Preussenthal, GM, Thomas, MK, Habener, JF. IPF-1/MODY4 gene missense mutation in an Italian family with type 2 and gestational diabetes. Metabol 2005;54:983–8. https://doi.org/10.1016/j.metabol.2005.01.037.Search in Google Scholar PubMed

37. Haaland, WC, Scaduto, DI, Maldonado, MR, Mansouri, DL, Nalini, R, Iyer, D, et al.. A-beta-subtype of ketosis-prone diabetes is not predominantly a monogenic diabetic syndrome. Diabetes Care 2009;32:873–7. https://doi.org/10.2337/dc08-1529.Search in Google Scholar PubMed PubMed Central

38. Edghill, EL, Khamis, A, Weedon, MN, Walker, M, Hitman, GA, McCarthy, MI, et al.. Sequencing PDX1 (insulin promoter factor 1) in 1788 UK individuals found 5% had a low frequency coding variant, but these variants are not associated with type 2 diabetes. Diabet Med 2011;28:681–4. https://doi.org/10.1111/j.1464-5491.2011.03269.x.Search in Google Scholar PubMed PubMed Central

39. Ang, SF, Lim, SC, Tan, CS, Fong, JC, Kon, WY, Lian, JX, et al.. A preliminary study to evaluate the strategy of combining clinical criteria and next generation sequencing (NGS) for the identification of monogenic diabetes among multi-ethnic Asians. Diabetes Res Clin Pract 2016;119:13–22. https://doi.org/10.1016/j.diabres.2016.06.008.Search in Google Scholar PubMed

40. 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

41. Sujjitjoon, J, Kooptiwut, S, Chongjaroen, N, Tangjittipokin, W, Plengvidhya, N, Yenchitsomanus, PT. Aberrant mRNA splicing of paired box 4 (PAX4) IVS7-1G> a mutation causing maturity-onset diabetes of the young, type 9. Acta Diabetol 2016;53:205–16. https://doi.org/10.1007/s00592-015-0760-x.Search in Google Scholar PubMed

42. Zamanfar, D, Keyhanian, E, Fomeshi, BM. A case report of a patient with maturity-onset diabetes of the young type 9. Clin Excell 2020;9:43–8.Search in Google Scholar

43. Torsvik, J, Johansson, S, Johansen, A, Ek, J, Minton, J, Ræder, H, et al.. Mutations in the VNTR of the carboxyl-ester lipase gene (CEL) are a rare cause of monogenic diabetes. Hum Genet 2010;127:55. https://doi.org/10.1007/s00439-009-0740-8.Search in Google Scholar PubMed

44. El Jellas, K, Dušátková, P, Haldorsen, IS, Molnes, J, Tjora, E, Johansson, BB, et al.. Two new mutations in the CEL gene causing diabetes and hereditary pancreatitis: how to correctly identify MODY8 cases. J Clin Endocrinol Metab 2021;107:e1455–66. https://doi.org/10.1210/clinem/dgab864.Search in Google Scholar PubMed PubMed Central

45. Zamanfar, DA. Type of diabetes called MODY2. Biomed J Sci Tech Res 2021;35:27917–8.10.26717/BJSTR.2021.35.005743Search in Google Scholar
Received: 2022-08-06
Accepted: 2022-08-24
Published Online: 2022-09-15
Published in Print: 2022-10-26

© 2022 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Original Articles
  3. Newborn screening for propionic, methylmalonic acidemia and vitamin B12 deficiency. Analysis of 588,793 newborns
  4. Use of letrozole to augment height outcome in pubertal boys: a retrospective chart review
  5. Study of the frequency and clinical features of maturity-onset diabetes in the young in the pediatric and adolescent diabetes population in Iran
  6. Iatrogenic hyperthyroidism in primary congenital hypothyroidism: prevalence and predictive factors
  7. Utility of head CT scan in treatment decisions for suspected cerebral edema in children with DKA
  8. Newborn screening and genetic variation of medium chain acyl-CoA dehydrogenase deficiency in the Chinese population
  9. Performance of glucagon stimulation test in diagnosing central adrenal insufficiency in children when utilising the Roche Elecsys® cortisol II assay: a pilot study
  10. Effects and dose-response relationship of exercise training on cardiometabolic risk factors in children with obesity
  11. Biochemical indicators of euthyroid sick syndrome in critically ill children
  12. Short Communication
  13. Parental marital relationship satisfaction predicts glycemic outcomes in children with type 1 diabetes
  14. Case Reports
  15. Late onset Bartter syndrome: Bartter syndrome type 2 presenting with isolated nephrocalcinosis and high parathyroid hormone levels mimicking primary hyperparathyroidism
  16. Three pediatric cases of symptomatic hyponatremia in Prader–Willi syndrome
  17. Identification of a novel mutation in FGFR1 gene in mother and daughter with Kallmann syndrome
  18. Exaggerated mini-puberty in a preterm girl: a case report and review of literature
  19. Diabetic ketoacidosis masquerading behind alkalemia an undiagnosed or missed variant of diabetic ketoacidosis
https://doi.org/10.1515/jpem-2022-0390
Keywords for this article
MODY subtypes; monogenic diabetes; next-generation sequencing; pediatric diabetes

Articles in the same Issue

  1. Frontmatter
  2. Original Articles
  3. Newborn screening for propionic, methylmalonic acidemia and vitamin B12 deficiency. Analysis of 588,793 newborns
  4. Use of letrozole to augment height outcome in pubertal boys: a retrospective chart review
  5. Study of the frequency and clinical features of maturity-onset diabetes in the young in the pediatric and adolescent diabetes population in Iran
  6. Iatrogenic hyperthyroidism in primary congenital hypothyroidism: prevalence and predictive factors
  7. Utility of head CT scan in treatment decisions for suspected cerebral edema in children with DKA
  8. Newborn screening and genetic variation of medium chain acyl-CoA dehydrogenase deficiency in the Chinese population
  9. Performance of glucagon stimulation test in diagnosing central adrenal insufficiency in children when utilising the Roche Elecsys® cortisol II assay: a pilot study
  10. Effects and dose-response relationship of exercise training on cardiometabolic risk factors in children with obesity
  11. Biochemical indicators of euthyroid sick syndrome in critically ill children
  12. Short Communication
  13. Parental marital relationship satisfaction predicts glycemic outcomes in children with type 1 diabetes
  14. Case Reports
  15. Late onset Bartter syndrome: Bartter syndrome type 2 presenting with isolated nephrocalcinosis and high parathyroid hormone levels mimicking primary hyperparathyroidism
  16. Three pediatric cases of symptomatic hyponatremia in Prader–Willi syndrome
  17. Identification of a novel mutation in FGFR1 gene in mother and daughter with Kallmann syndrome
  18. Exaggerated mini-puberty in a preterm girl: a case report and review of literature
  19. Diabetic ketoacidosis masquerading behind alkalemia an undiagnosed or missed variant of diabetic ketoacidosis
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