Abstract
Background: Maturity-onset diabetes of the youth (MODY), is a genetically and clinically heterogeneous group of diseasesand is often misdiagnosed as type 1 or type 2 diabetes. The aim of this study is to investigate both novel and proven mutations of 11 MODY genes in Turkish children by using targeted next generation sequencing.
Methods: A panel of 11 MODY genes were screened in 43 children with MODY diagnosed by clinical criterias. Studies of index cases was done with MISEQ-ILLUMINA, and family screenings and confirmation studies of mutations was done by Sanger sequencing.
Results: We identified 28 (65%) point mutations among 43 patients. Eighteen patients have GCK mutations, four have HNF1A, one has HNF4A, one has HNF1B, two have NEUROD1, one has PDX1 gene variations and one patient has both HNF1A and HNF4A heterozygote mutations.
Conclusions: This is the first study including molecular studies of 11 MODY genes in Turkish children. GCK is the most frequent type of MODY in our study population. Very high frequency of novel mutations (42%) in our study population, supports that in heterogenous disorders like MODY sequence analysis provides rapid, cost effective and accurate genetic diagnosis.
References
1. Ledermann HM. Is maturity onset diabetes at young age (MODY) more common in Europe than previously assumed? Lancet 1995;345:648.10.1016/S0140-6736(95)90548-0Search in Google Scholar
2. Bonnefond A, Philippe J, Durand E, Dechaume A, Huyvaert M, Montagne L, et al. Whole-exome sequencing and high through put genotyping identified KCNJ11 as the thirteenth MODY gene. PLoS One 2012;7:e37423.10.1371/journal.pone.0037423Search in Google Scholar PubMed PubMed Central
3. Murphy R, Ellard S, Hattersley AT. Clinical implications of a molecular genetic classification of monogenic beta-cell diabetes. Nat Clin Pract Endocrinol Metab 2008;4:200–13.10.1038/ncpendmet0778Search in Google Scholar PubMed
4. van der Zwaag AM, Weinreich SS, Bosma AR, Rigter T, Losekoot M, Henneman L, et al. Current and best practices of genetic testing for maturity onset diabetes of the young: views of professional experts. Public Health Genomics 2015;18:52–9.10.1159/000367963Search in Google Scholar PubMed
5. Naylor RN, John PM, Winn AN, Carmody D, Greeley SA, Philipson LH, et al. Cost-effectiveness of MODY genetic testing: translating genomic advances into practical health applications. Diabetes Care 2014;37:202–9.10.2337/dc13-0410Search in Google Scholar PubMed PubMed Central
6. Chapla A, Mruthyunjaya MD, Asha HS, Varghese D, Varshney M, Vasan SK, et al. Maturity onset diabetes of the young in India – a distinctive mutation pattern identified through targeted next-generation sequencing. Clin Endocrinol (Oxf) 2015;82:533–42.10.1111/cen.12541Search in Google Scholar PubMed
7. Alkorta-Aranburu G, Carmody D, Cheng YW, Nelakuditi V, Ma L, Dickens JT, et al. Phenotypic heterogeneity in monogenic diabetes: The clinical and diagnostic utility of a gene panel-based next-generation sequencing approach. Mol Genet Metab 2014;113:315–20.10.1016/j.ymgme.2014.09.007Search in Google Scholar PubMed PubMed Central
8. Thanabalasingham G, Owen KR. Diagnosis and management of maturity onset diabetes of the young (MODY). Br Med J 2011;343:d6044.10.1136/bmj.d6044Search in Google Scholar PubMed
9. Shields BM, Hicks S, Shepherd MH, Colclough K, Hattersley AT, Ellard S. Maturity-onset diabetes of the young (MODY): how many cases are we missing? Diabetologia 2010;53:2504–8.10.1007/s00125-010-1799-4Search in Google Scholar PubMed
10. Osbak KK, Colclough K, Saint-Martin C, Beer NL, Bellanné-Chantelot C, Ellard S, et al. Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. Hum Mutat 2009;30:1512–26.10.1002/humu.21110Search in Google Scholar PubMed
11. Massa O, Meschi F, Cuesta-Munoz A, Caumo A, Cerutti F, Toni S, et al. High prevalence of glucokinase mutations in Italian children with MODY. Influence on glucose tolerance, first-phase insulin response, insulin sensitivity and BMI. Diabetes Study Group of the Italian Society of Paediatric Endocrinology and Diabetes (SIEDP). Diabetologia 2001;44:898–905.10.1007/s001250100530Search in Google Scholar PubMed
12. Awa WL, Thon A, Raile K, Grulich-Henn J, Meissner T, Schober E, et al. Genetic and clinical characteristics of patients with HNF1A gene variations from the German-Austrian DPV database. Eur J Endocrinol 2011;164:513–20.10.1530/EJE-10-0842Search in Google Scholar PubMed
13. Urhammer SA, Fridberg M, Hansen T, Rasmussen SK, Møller AM, Clausen JO, et al. A prevalent amino acid polymorphism at codon 98 in the hepatocyte nuclear factor-1 alpha gene is associated with reduced serum C-peptide and insulin responses to an oral glucose challenge. Diabetes 1997;46:912–6.10.2337/diab.46.5.912Search in Google Scholar PubMed
14. Glucksmann MA, Lehto M, Tayber O, Scotti S, Berkemeier L, Pulido JC, et al. Novel mutations and a mutational hotspot in the MODY3 gene. Diabetes 1997;46:1081–6.10.2337/diabetes.46.6.1081Search in Google Scholar
15. Malecki MT, Jhala US, Antonellis A, Fields L, Doria A, Orban T, et al. Mutations in NEUROD1 are associated with the development of type 2 diabetes mellitus. Nat Genet 1999;23:323–8.10.1038/15500Search in Google Scholar PubMed
16. Mota AJ, Brüggemann S, Costa FF. MODY 2: mutation identification and molecular ancestry in a Brazilian family. Gene 2013;512:486–91.10.1016/j.gene.2012.10.013Search in Google Scholar PubMed
17. Mantovani V, Salardi S, Cerreta V, Bastia D, Cenci M, Ragni L, et al. Identification of eight novel glucokinase mutations in Italian children with maturity-onset diabetes of the young. Hum Mutat 2003;22:338.10.1002/humu.9179Search in Google Scholar PubMed
18. Pruhova S, Dusatkova P, Sumnik Z, Kolouskova S, Pedersen O, Hansen T, et al. Glucokinase diabetes in 103 families from a country-based study in the Czech Republic: geographically restricted distribution of two prevalent GCK mutations. Pediatr Diabetes 2010;11:529–35.10.1111/j.1399-5448.2010.00646.xSearch in Google Scholar PubMed
19. Capuano M, Garcia-Herrero CM, Tinto N, Carluccio C, Capobianco V, Coto I, et al. Glucokinase (GCK) mutations and their characterization in MODY2 children of southern Italy. PLoSOne 2012;7:e38906.10.1371/journal.pone.0038906Search in Google Scholar PubMed PubMed Central
20. Owen KR. Monogenic diabetes: old and new approaches to diagnosis. Clin Med 2013;13:278–81.10.7861/clinmedicine.13-3-278Search in Google Scholar PubMed PubMed Central
21. Tattersall R. Maturity-onset diabetes of the young: a clinical history. Diabet Med 1998;15:11–4.10.1002/(SICI)1096-9136(199801)15:1<11::AID-DIA561>3.0.CO;2-0Search in Google Scholar
22. 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;51:546–53.10.1007/s00125-008-0942-ySearch in Google Scholar
23. 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. Diab care 2009;32:1864–6.10.2337/dc08-2018Search in Google Scholar
24. Cuesta-Munoz AL, Tuomi T, Cobo-Vuilleumier N, Koskela H, Odili S, Stride A, et al. Clinical heterogeneity in monogenic diabetes caused by mutations in the glucokinase gene (GCK MODY). Diab care 2010;33:290–2.10.2337/dc09-0681Search in Google Scholar
25. Bingham C, Hattersley AT. Renal cysts and diabetes syndrome resulting from mutations in hepatocyte nuclear factor-1 beta. Nephrol Dial Transplant 2004;19:2703–8.10.1093/ndt/gfh348Search in Google Scholar
26. Dusatkova P, Fang M, Pruhova S, Gjesing AP, Cinek O, Hansen T, et al. Lessons from whole-exome sequencing in MODYX families. Diabetes Res Clin Pract 2014;104:e72–4.10.1016/j.diabres.2014.03.008Search in Google Scholar
27. Pearson ER, Badman MK, Lockwood CR, Clark PM, Ellard S, Bingham C, et al. Contrasting diabetes pheno types associated with hepatocyte nuclear factor-1 alpha and 1 beta mutations. Diabetes Care 2004;27:1102–7.10.2337/diacare.27.5.1102Search in Google Scholar
28. Naya FJ, Huang HP, Qiu Y, Mutoh H, DeMayo FJ, Leiter AB, et al. Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuroD deficient mice. Genes Dev 1997;11:2323–34.10.1101/gad.11.18.2323Search in Google Scholar
29. Miyata T, Maeda T, Lee JE. NeuroD is required for differentiation of the granule cells in the cerebellum and hippocampus. Genes Dev 1999;13:1647–52.10.1101/gad.13.13.1647Search in Google Scholar
30. Liu M, Pleasure SJ, Collins AE, Noebels JL, Naya FJ, Tsai MJ, et al. Loss of BETA2/NeuroD leads to malformation of the dentate gyrus and epilepsy. Proc Natl Acad Sci USA 2000;97:865–70.10.1073/pnas.97.2.865Search in Google Scholar
31. Hui H, Perfetti R. Pancreas duodenum homeobox 1 regulates pancreas development during embryogenesis and islet cell function in adulthood. Eur J Endocrinol 2002;146:129–41.10.1530/eje.0.1460129Search in Google Scholar PubMed
32. Elbein SC, Karim MA. Does the aspartic acid to asparagine substitution at position 76 in the pancreas duodenum homeobox gene (PDX1) cause late-onset type 2 diabetes? Diabetes Care 2004;27:1968–73.10.2337/diacare.27.8.1968Search in Google Scholar PubMed
33. Hansen L, Urioste S, Petersen HV, Jensen JN, Eiberg H, Barbetti F, et al. Missense mutations in the human insulin promoter factor-1 gene and their relation to maturity-onset diabetes of the young and late-onset type 2 diabetes mellitus in caucasians. J Clin Endocrinol Metab 2000;85:1323–6.Search in Google Scholar
34. 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. Metabolism 2005;54:983–8.10.1016/j.metabol.2005.01.037Search in Google Scholar PubMed
35. Forlani G, Zucchini S, Di Rocco A, Di Luzio R, Scipione M, Marasco E, et al. Double heterozygous mutations involving both HNF1A/MODY3 and HNF4A/MODY1 genes: a case report. Diabetes Care 2010;33:2336–8.10.2337/dc10-0561Search in Google Scholar PubMed PubMed Central
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