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Journal of Pediatric Endocrinology and Metabolism

Editor-in-Chief: Kiess, Wieland

Ed. by Bereket, Abdullah / Darendeliler, Feyza / Dattani, Mehul / Gustafsson, Jan / Luo, Fei Hong / Mericq, Veronica / Toppari, Jorma


IMPACT FACTOR 2017: 1.086

CiteScore 2018: 1.22

SCImago Journal Rank (SJR) 2018: 0.507
Source Normalized Impact per Paper (SNIP) 2018: 0.562

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2191-0251
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Volume 28, Issue 11-12

Issues

Molecular diagnosis of maturity-onset diabetes of the young (MODY) in Turkish children by using targeted next-generation sequencing

Ahmet Anık
  • Corresponding author
  • Faculty of Medicine, Department of Pediatric Endocrinology, Dokuz Eylul University, İzmir, Turkey
  • Email
  • Other articles by this author:
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/ Gönül Çatlı
  • Faculty of Medicine, Department of Pediatric Endocrinology, Dokuz Eylul University, İzmir, Turkey
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  • De Gruyter OnlineGoogle Scholar
/ Ayhan Abacı
  • Faculty of Medicine, Department of Pediatric Endocrinology, Dokuz Eylul University, İzmir, Turkey
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Erkan Sarı / Ediz Yeşilkaya / Hüseyin Anıl Korkmaz / Korcan Demir
  • Faculty of Medicine, Department of Pediatric Endocrinology, Dokuz Eylul University, İzmir, Turkey
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Ayça Altıncık / Hale Ünver Tuhan
  • Faculty of Medicine, Department of Pediatric Endocrinology, Dokuz Eylul University, İzmir, Turkey
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  • De Gruyter OnlineGoogle Scholar
/ Sefa Kızıldağ
  • Faculty of Medicine, Department of Medical Biology and Medical Genetics, Dokuz Eylul University, İzmir, Turkey
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  • De Gruyter OnlineGoogle Scholar
/ Behzat Özkan / Serdar Ceylaner / Ece Böber
  • Faculty of Medicine, Department of Pediatric Endocrinology, Dokuz Eylul University, İzmir, Turkey
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2015-07-30 | DOI: https://doi.org/10.1515/jpem-2014-0430

Abstract

Aim: To perform molecular analysis of pediatric maturity onset diabetes of the young (MODY) patients by next-generation sequencing, which enables simultaneous analysis of multiple genes in a single test, to determine the genetic etiology of a group of Turkish children clinically diagnosed as MODY, and to assess genotype-phenotype relationship.

Methods: Forty-two children diagnosed with MODY and their parents were enrolled in the study. Clinical and laboratory characteristics of the patients at the time of diagnosis were obtained from hospital records. Molecular analyses of GCK, HNF1A, HNF4A, HNF1B, PDX1, NEUROD1, KLF11, CEL, PAX4, INS, and BLK genes were performed on genomic DNA by using next-generation sequencing. Pathogenicity for novel mutations was assessed by bioinformatics prediction software programs and segregation analyses.

Results: A mutation in MODY genes was identified in 12 (29%) of the cases. GCK mutations were detected in eight cases, and HNF1B, HNF1A, PDX1, and BLK mutations in the others. We identified five novel missense mutations – three in GCK (p.Val338Met, p.Cys252Ser, and p.Val86Ala), one in HNF1A (p.Cys241Ter), and one in PDX1 (p.Gly55Asp), which we believe to be pathogenic.

Conclusion: The results of this study showed that mutations in the GCK gene are the leading cause of MODY in our population. Moreover, genetic diagnosis could be made in 29% of Turkish patients, and five novel mutations were identified.

Keywords: childhood; MODY; next-generation sequencing

References

  • 1.

    Henzen C. Monogenic diabetes mellitus due to defects in insulin secretion. Swiss Med Wkly 2012;142:w13690.Google Scholar

  • 2.

    Fajans SS, Bell GI. MODY: history, genetics, pathophysiology, and clinical decision making. Diabetes Care 2011;34:1878–84.CrossrefWeb of SciencePubMedGoogle Scholar

  • 3.

    Molven A, Njolstad PR. Role of molecular genetics in transforming diagnosis of diabetes mellitus. Expert Rev Mol Diagn 2011;11:313–20.PubMedGoogle Scholar

  • 4.

    Boutin P, Vasseur F, Samson C, Wahl C, Froguel P. Routine mutation screening of HNF-1alpha and GCK genes in MODY diagnosis: how effective are the techniques of DHPLC and direct sequencing used in combination? Diabetologia 2001;44:775–8.PubMedCrossrefGoogle Scholar

  • 5.

    Schober E, Rami B, Grabert M, Thon A, Kapellen T, et al. Phenotypical aspects of maturity-onset diabetes of the young (MODY diabetes) in comparison with Type 2 diabetes mellitus (T2DM) in children and adolescents: experience from a large multicentre database. Diabet Med 2009;26:466–73.PubMedCrossrefGoogle Scholar

  • 6.

    Pearson ER, Starkey BJ, Powell RJ, Gribble FM, Clark PM, et al. Genetic cause of hyperglycaemia and response to treatment in diabetes. Lancet 2003;362:1275–81.Google Scholar

  • 7.

    Shepherd M, Shields B, Ellard S, Rubio-Cabezas O, Hattersley AT. A genetic diagnosis of HNF1A diabetes alters treatment and improves glycaemic control in the majority of insulin-treated patients. Diabet Med 2009;26:437–41.CrossrefGoogle Scholar

  • 8.

    Johansen Taber KA, Dickinson BD, Wilson M. The promise and challenges of next-generation genome sequencing for clinical care. J Am Med Assoc Intern Med 2014;174:275–80.Google Scholar

  • 9.

    Ellard S, Lango Allen H, De Franco E, Flanagan SE, Hysenaj G, et al. Improved genetic testing for monogenic diabetes using targeted next-generation sequencing. Diabetologia 2013;56:1958–63.CrossrefWeb of SciencePubMedGoogle Scholar

  • 10.

    Alkorta-Aranburu G, Carmody D, Cheng YW, Nelakuditi V, Ma L, 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.CrossrefGoogle Scholar

  • 11.

    Kuczmarski RJ, Ogden CL, Guo SS, Grummer-Strawn LM, Flegal KM, et al. 2000 CDC Growth Charts for the United States: methods and development. Vital Health Stat 11 2002;246:1–190.Google Scholar

  • 12.

    American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2005;28(Suppl 1):S37–42.CrossrefWeb of ScienceGoogle Scholar

  • 13.

    Wolfsdorf J, Craig ME, Daneman D, Dunger D, Edge J, et al. Diabetic ketoacidosis in children and adolescents with diabetes. Pediatr Diabetes 2009;10(Suppl 12):118–33.CrossrefPubMedGoogle Scholar

  • 14.

    Guazzini B, Gaffi D, Mainieri D, Multari G, Cordera R, et al. Three novel missense mutations in the glucokinase gene (G80S; E221K; G227C) in Italian subjects with maturity-onset diabetes of the young (MODY). Mutations in brief no. 162. Online. Hum Mutat 1998;12:136.CrossrefGoogle Scholar

  • 15.

    Codner E, Rocha A, Deng L, Martinez-Aguayo A, Godoy C, 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.Web of ScienceCrossrefPubMedGoogle Scholar

  • 16.

    Gragnoli C, Cockburn BN, Chiaramonte F, Gorini A, Marietti G, et al. Early-onset type II diabetes mellitus in Italian families due to mutations in the genes encoding hepatic nuclear factor 1 alpha and glucokinase. Diabetologia 2001;44:1326–9.CrossrefPubMedGoogle Scholar

  • 17.

    Garin I, Rica I, Estalella I, Oyarzabal M, Rodriguez-Rigual M, et al. Haploinsufficiency at GCK gene is not a frequent event in MODY2 patients. Clin Endocrinol 2008;68:873–8.Google Scholar

  • 18.

    Lorini R, Klersy C, d’Annunzio G, Massa O, Minuto N, 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.CrossrefWeb of ScienceGoogle Scholar

  • 19.

    Bellanne-Chantelot C, Clauin S, Chauveau D, Collin P, Daumont M, 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.Google Scholar

  • 20.

    Borowiec M, Liew CW, Thompson R, Boonyasrisawat W, Hu J, et al. Mutations at the BLK locus linked to maturity onset diabetes of the young and beta-cell dysfunction. Proc Natl Acad Sci USA 2009;106:14460–5.CrossrefWeb of ScienceGoogle Scholar

  • 21.

    Estalella I, Rica I, Perez de Nanclares G, Bilbao JR, Vazquez JA, et al. Mutations in GCK and HNF-1alpha explain the majority of cases with clinical diagnosis of MODY in Spain. Clin Endocrinol 2007;67:538–46.Google Scholar

  • 22.

    Pruhova S, Ek J, Lebl J, Sumnik Z, Saudek F, et al. Genetic epidemiology of MODY in the Czech republic: new mutations in the MODY genes HNF-4alpha, GCK and HNF-1alpha. Diabetologia 2003;46:291–5.PubMedGoogle Scholar

  • 23.

    Xu JY, Dan QH, Chan V, Wat NM, Tam S, et al. Genetic and clinical characteristics of maturity-onset diabetes of the young in Chinese patients. Eur J Hum Genet 2005;13:422–7.PubMedCrossrefGoogle Scholar

  • 24.

    Hwang JS, Shin CH, Yang SW, Jung SY, Huh N. Genetic and clinical characteristics of Korean maturity-onset diabetes of the young (MODY) patients. Diabetes Res Clin Pract 2006;74:75–81.CrossrefPubMedGoogle Scholar

  • 25.

    Rubio-Cabezas O, Hattersley AT, Njolstad PR, Mlynarski W, Ellard S, et al. The diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabetes 2014;15(Suppl 20):47–64.CrossrefGoogle Scholar

  • 26.

    Thanabalasingham G, Owen KR. Diagnosis and management of maturity onset diabetes of the young (MODY). Br Med J 2011;343:d6044.Google Scholar

  • 27.

    Osbak KK, Colclough K, Saint-Martin C, Beer NL, Bellanne-Chantelot C, 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.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 28.

    McDonald TJ, Ellard S. Maturity onset diabetes of the young: identification and diagnosis. Ann Clin Biochem 2013; 50(Pt 5):403–15.CrossrefPubMedWeb of ScienceGoogle Scholar

  • 29.

    Martin D, Bellanne-Chantelot C, Deschamps I, Froguel P, Robert JJ, et al. 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.CrossrefWeb of SciencePubMedGoogle Scholar

  • 30.

    Chen YZ, Gao Q, Zhao XZ, Chen YZ, Bennett CL, et al. Systematic review of TCF2 anomalies in renal cysts and diabetes syndrome/maturity onset diabetes of the young type 5. Chin Med J (Engl) 2010;123:3326–33.Google Scholar

  • 31.

    Ulinski T, Lescure S, Beaufils S, Guigonis V, Decramer S, et al. Renal phenotypes related to hepatocyte nuclear factor-1beta (TCF2) mutations in a pediatric cohort. J Am Soc Nephrol 2006;17:497–503.Google Scholar

  • 32.

    Bellanne-Chantelot C, Carette C, Riveline JP, Valero R, Gautier JF, et al. The type and the position of HNF1A mutation modulate age at diagnosis of diabetes in patients with maturity-onset diabetes of the young (MODY)-3. Diabetes 2008;57:503–8.CrossrefWeb of ScienceGoogle Scholar

  • 33.

    Moller AM, Dalgaard LT, Pociot F, Nerup J, Hansen T, et al. Mutations in the hepatocyte nuclear factor-1alpha gene in Caucasian families originally classified as having Type I diabetes. Diabetologia 1998;41:1528–31.CrossrefPubMedGoogle Scholar

  • 34.

    Gragnoli C, Stanojevic V, Gorini A, Von Preussenthal GM, Thomas MK, et al. IPF-1/MODY4 gene missense mutation in an Italian family with type 2 and gestational diabetes. Metabolism 2005;54:983–8.Google Scholar

  • 35.

    Fajans SS, Bell GI, Paz VP, Below JE, Cox NJ, et al. Obesity and hyperinsulinemia in a family with pancreatic agenesis and MODY caused by the IPF1 mutation Pro63fsX60. Transl Res 2010;156:7–14.Web of ScienceGoogle Scholar

  • 36.

    Bonnefond A, Yengo L, Philippe J, Dechaume A, Ezzidi I, et al. Reassessment of the putative role of BLK-p.A71T loss-of-function mutation in MODY and type 2 diabetes. Diabetologia 2013;56:492–6.Web of ScienceCrossrefGoogle Scholar

  • 37.

    Pihoker C, Gilliam LK, Ellard S, Dabelea D, Davis C, et al. Prevalence, characteristics and clinical diagnosis of maturity onset diabetes of the young due to mutations in HNF1A, HNF4A, and glucokinase: results from the SEARCH for Diabetes in Youth. J Clin Endocrinol Metab 2013;98:4055–62.Web of ScienceGoogle Scholar

About the article

Corresponding author: Ahmet Anık, MD, Faculty of Medicine, Department of Pediatric Endocrinology, Dokuz Eylul University, 35340, Balçova, İzmir, Turkey, Phone: +90-232-4126081, Fax: +90-232-4126001, E-mail:


Received: 2014-10-13

Accepted: 2015-06-22

Published Online: 2015-07-30

Published in Print: 2015-11-01


Citation Information: Journal of Pediatric Endocrinology and Metabolism, Volume 28, Issue 11-12, Pages 1265–1271, ISSN (Online) 2191-0251, ISSN (Print) 0334-018X, DOI: https://doi.org/10.1515/jpem-2014-0430.

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