Monogenic Diabetes

  • Katharine R. OwenEmail author
Reference work entry
Part of the Endocrinology book series (ENDOCR)


Monogenic forms of diabetes can be associated with diabetes diagnosed in neonatal life or in young adulthood.

The commonest presentation of monogenic diabetes is maturity-onset diabetes of the young (MODY), which typically presents in young adult life with familial, non-autoimmune diabetes without insulin resistance. HNF1A and GCK mutations account for most cases.

Mitochondrial diabetes presents at a similar age with diabetes associated with deafness, myopathy, and neurological features.

In the first 6 months of life, diabetes is nearly always caused by single gene mutations. Neonatal diabetes is highly heterogeneous, but the commonest causes are mutations in KCNJ11 and ABCC8 encoding the beta-cell KATP channel components and methylation defects in the chromosome 6q24 region.

The most important reason for diagnosing monogenic diabetes is that the genetic aetiology alters treatment. Mutations in HNF1A, HNF4A, ABCC8, and KCNJ11 all lead to diabetes responsive to sulfonylurea therapy, while GCK-MODY does not require treatment.

When diabetes arises as part of a multisystem disorder such as in Wolcott-Rallison syndrome or HNF1B-MODY, the genetic diagnosis may give important insight into prognosis and development of other features.

New sequencing technologies such as exome sequencing can be used to search for new genes which cause diabetes, but interpreting novel genetic variants in both familiar and less well-known genes remains extremely challenging.


Monogenic diabetes MODY Neonatal diabetes Mitochondrial diabetes Precision medicine 


  1. American Diabetes, Association. 2. Classification and diagnosis of diabetes. Diabetes Care. 2017;40(Suppl 1):S11–24.CrossRefGoogle Scholar
  2. Ashcroft FM, Puljung MC, Vedovato N. Neonatal diabetes and the KATP Channel: from mutation to therapy. Trends Endocrinol Metab. 2017;28(5):377–87.CrossRefGoogle Scholar
  3. Babiker T, et al. Successful transfer to sulfonylureas in KCNJ11 neonatal diabetes is determined by the mutation and duration of diabetes. Diabetologia. 2016;59(6):1162–6.CrossRefGoogle Scholar
  4. Bacon S, et al. Successful maintenance on sulfonylurea therapy and low diabetes complication rates in a HNF1A-MODY cohort. Diabet Med. 2015;33:976.CrossRefGoogle Scholar
  5. Battaglia D, et al. Glyburide ameliorates motor coordination and glucose homeostasis in a child with diabetes associated with the KCNJ11/S225T, del226-232 mutation. Pediatr Diabetes. 2012;13(8):656–60.CrossRefGoogle Scholar
  6. Bellanne-Chantelot C, et al. Clinical spectrum associated with hepatocyte nuclear factor-1beta mutations. Ann Intern Med. 2004;140(7):510–7.CrossRefGoogle Scholar
  7. Bellanne-Chantelot 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(11):3126–32.CrossRefGoogle Scholar
  8. Bellanne-Chantelot C, et al. Clinical characteristics and diagnostic criteria of maturity-onset diabetes of the young (MODY) due to molecular anomalies of the HNF1A gene. J Clin Endocrinol Metab. 2011;96(8):E1346–51.CrossRefGoogle Scholar
  9. Bellanne-Chantelot C, et al. High-sensitivity C-reactive protein does not improve the differential diagnosis of HNF1A-MODY and familial young-onset type 2 diabetes: a grey zone analysis. Diabetes Metab. 2016;42(1):33–7.CrossRefGoogle Scholar
  10. Bennett CL, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. 2001;27(1):20–1.CrossRefGoogle Scholar
  11. Boesgaard TW, et al. Further evidence that mutations in INS can be a rare cause of maturity-onset diabetes of the young (MODY). BMC Med Genet. 2010;11:42.CrossRefGoogle Scholar
  12. Bonnycastle LL, et al. Autosomal dominant diabetes arising from a Wolfram syndrome 1 mutation. Diabetes. 2013;62(11):3943–50.CrossRefGoogle Scholar
  13. Clissold RL, et al. Chromosome 17q12 microdeletions but not intragenic HNF1B mutations link developmental kidney disease and psychiatric disorder. Kidney Int. 2016;90(1):203–11.CrossRefGoogle Scholar
  14. De Franco E, et al. The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort study. Lancet. 2015;386(9997):957–63.CrossRefGoogle Scholar
  15. Edghill EL, et al. Insulin mutation screening in 1,044 patients with diabetes: mutations in the INS gene are a common cause of neonatal diabetes but a rare cause of diabetes diagnosed in childhood or adulthood. Diabetes. 2008;57(4):1034–42.CrossRefGoogle Scholar
  16. Eide SA, et al. Prevalence of HNF1A (MODY3) mutations in a Norwegian population (the HUNT2 study). Diabet Med. 2008;25(7):775–81.CrossRefGoogle Scholar
  17. Ellard S, et al. Best practice guidelines for the molecular genetic diagnosis of maturity-onset diabetes of the young. Diabetologia. 2008;51(4):546–53.CrossRefGoogle Scholar
  18. Ellard S, et al. Improved genetic testing for monogenic diabetes using targeted next-generation sequencing. Diabetologia. 2013;56(9):1958–63.CrossRefGoogle Scholar
  19. Estalella I, et al. Mutations in GCK and HNF-1alpha explain the majority of cases with clinical diagnosis of MODY in Spain. Clin Endocrinol. 2007;67(4):538–46.Google Scholar
  20. Flanagan S, De Franco E. Monogenic causes of pancreatic agenesis. 2015; Diapedia 4105491820 rev. no. 2. Available from Scholar
  21. Flanagan SE, et al. Mutations in ATP-sensitive K+ channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood. Diabetes. 2007;56(7):1930–7.CrossRefGoogle Scholar
  22. Flanagan SE, et al. Analysis of transcription factors key for mouse pancreatic development establishes NKX2-2 and MNX1 mutations as causes of neonatal diabetes in man. Cell Metab. 2014;19(1):146–54.CrossRefGoogle Scholar
  23. Flannick J, et al. Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes. Nat Genet. 2013;45(11):1380–5.CrossRefGoogle Scholar
  24. Froguel P, et al. Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus. Nature. 1992;356:162–4.CrossRefGoogle Scholar
  25. Garin I, et al. Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis. Proc Natl Acad Sci U S A. 2010;107(7):3105–10.CrossRefGoogle Scholar
  26. Gloyn AL, et al. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N Engl J Med. 2004;350(18):1838–49.CrossRefGoogle Scholar
  27. Hattersley AT, et al. Mutations in the glucokinase gene of the fetus result in reduced birth weight. Nat Genet. 1998;19:268–70.CrossRefGoogle Scholar
  28. Iafusco D, et al. Permanent diabetes mellitus in the first year of life. Diabetologia. 2002;45(6):798–804.CrossRefGoogle Scholar
  29. Iafusco D, et al. Minimal incidence of neonatal/infancy onset diabetes in Italy is 1:90,000 live births. Acta Diabetol. 2012;49(5):405–8.CrossRefGoogle Scholar
  30. Izumi T, et al. Dominant negative pathogenesis by mutant proinsulin in the Akita diabetic mouse. Diabetes. 2003;52(2):409–16.CrossRefGoogle Scholar
  31. Johansson S, et al. Exome sequencing and genetic testing for MODY. PLoS One. 2012;7(5):e38050.CrossRefGoogle Scholar
  32. Johansson BB, 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. Diabetologia. 2017;60(4):625–35.CrossRefGoogle Scholar
  33. Johnson MB, et al. Recessively inherited LRBA mutations cause autoimmunity presenting as neonatal diabetes. Diabetes. 2017;66(8):2316–22.CrossRefGoogle Scholar
  34. Kanthimathi S, et al. Identification and molecular characterization of HNF1B gene mutations in Indian diabetic patients with renal abnormalities. Ann Hum Genet. 2015;79(1):10–9.CrossRefGoogle Scholar
  35. Kavvoura F, et al. Reclassification of diabetes etiology in a family with multiple diabetes phenotypes. J Clin Endocrinol Metab. 2014;99:E1067. Scholar
  36. Kropff J, et al. Prevalence of monogenic diabetes in young adults: a community-based, cross-sectional study in Oxfordshire, UK. Diabetologia. 2011;54(5):1261–3.CrossRefGoogle Scholar
  37. Laver TW, et al. The common p.R114W HNF4A mutation causes a distinct clinical subtype of monogenic diabetes. Diabetes. 2016;65(10):3212–7.CrossRefGoogle Scholar
  38. Ledermann HM. Maturity-onset diabetes of the young (MODY) at least ten times more common in Europe than previously assumed? Diabetologia. 1995;38(12):1482.CrossRefGoogle Scholar
  39. Lek M, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536(7616):285–91.CrossRefGoogle Scholar
  40. Lorini R, et al. Maturity-onset diabetes of the young in children with incidental hyperglycemia: a multicenter Italian study of 172 families. Diabetes Care. 2009;32(10):1864–6.CrossRefGoogle Scholar
  41. MacArthur DG, et al. Guidelines for investigating causality of sequence variants in human disease. Nature. 2014;508(7497):469–76.CrossRefGoogle Scholar
  42. McDonald TJ, et al. High-sensitivity CRP discriminates HNF1A-MODY from other subtypes of diabetes. Diabetes Care. 2011;34(8):1860–2.CrossRefGoogle Scholar
  43. Molven A, et al. Mutations in the insulin gene can cause MODY and autoantibody-negative type 1 diabetes. Diabetes. 2008;57(4):1131–5.CrossRefGoogle Scholar
  44. Moritani M, et al. Identification of monogenic gene mutations in Japanese subjects diagnosed with type 1B diabetes between >5 and 15.1 years of age. J Pediatr Endocrinol Metab. 2016;29(9):1047–54.CrossRefGoogle Scholar
  45. Murphy R, et al. Clinical features, diagnosis and management of maternally inherited diabetes and deafness (MIDD) associated with the 3243A>G mitochondrial point mutation. Diabet Med. 2008;25(4):383–99.CrossRefGoogle Scholar
  46. Njolstad PR, et al. Permanent neonatal diabetes caused by glucokinase deficiency: inborn error of the glucose-insulin signaling pathway. Diabetes. 2003;52(11):2854–60.CrossRefGoogle Scholar
  47. Owen KR, et al. Assessment of high-sensitivity C-reactive protein levels as diagnostic discriminator of maturity-onset diabetes of the young due to HNF1A mutations. Diabetes Care. 2010;33(9):1919–24.CrossRefGoogle Scholar
  48. Panzram G, Adolph W. Heterogeneity of maturity onset diabetes at young age (MODY). Lancet. 1981;2(8253):986.CrossRefGoogle Scholar
  49. Patch AM, et al. Mutations in the ABCC8 gene encoding the SUR1 subunit of the KATP channel cause transient neonatal diabetes, permanent neonatal diabetes or permanent diabetes diagnosed outside the neonatal period. Diabetes Obes Metab. 2007;9(Suppl 2):28–39.CrossRefGoogle Scholar
  50. Patel K, Laakso M, Stancakova A, Laver TW, Colclough K, Johnson MB, Kettunen J, Tuomi T, Cnop M, Shepherd MH, Flanagan SE, Ellard S, Hattersley AT, Weedon MN. Heterozygous RFX6 protein truncating variants cause Maturity-Onset Diabetes of the Young (MODY) with reduced penetrance. Nat Commun. 2017;8:888. BioRxiv beta.CrossRefGoogle Scholar
  51. Pearson ER, et al. Genetic cause of hyperglycaemia and response to treatment in diabetes. Lancet. 2003;362(9392):1275–81.CrossRefGoogle Scholar
  52. Pearson ER, et al. Switching from insulin to oral sulfonylureas in patients with diabetes due to Kir6.2 mutations. N Engl J Med. 2006;355(5):467–77.CrossRefGoogle Scholar
  53. Pearson ER, et al. Macrosomia and hyperinsulinaemic hypoglycaemia in patients with heterozygous mutations in the HNF4A gene. PLoS Med. 2007;4(4):e118.CrossRefGoogle Scholar
  54. Pihoker 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(10):4055–62.CrossRefGoogle Scholar
  55. Prudente S, et al. Loss-of-function mutations in APPL1 in familial diabetes mellitus. Am J Hum Genet. 2015;97(1):177–85.CrossRefGoogle Scholar
  56. Raeder H, et al. Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction. Nat Genet. 2006;38(1):54–62.CrossRefGoogle Scholar
  57. Raile K, et al. Expanded clinical spectrum in hepatocyte nuclear factor 1b-maturity-onset diabetes of the young. J Clin Endocrinol Metab. 2009;94(7):2658–64.CrossRefGoogle Scholar
  58. Rasmussen M, et al. 17q12 deletion and duplication syndrome in Denmark-a clinical cohort of 38 patients and review of the literature. Am J Med Genet A. 2016;170(11):2934–42.CrossRefGoogle Scholar
  59. Rubio-Cabezas O, et al. Homozygous mutations in NEUROD1 are responsible for a novel syndrome of permanent neonatal diabetes and neurological abnormalities. Diabetes. 2010;59(9):2326–31.CrossRefGoogle Scholar
  60. Rubio-Cabezas O, et al. ISPAD clinical practice consensus guidelines 2014. The diagnosis and management of monogenic diabetes in children and adolescents. Pediatr Diabetes. 2014;15(Suppl 20):47–64.CrossRefGoogle Scholar
  61. Senee V, et al. Wolcott-Rallison syndrome: clinical, genetic, and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity. Diabetes. 2004;53(7):1876–83.CrossRefGoogle Scholar
  62. Shepherd M, et al. A genetic diagnosis of HNF1A diabetes alters treatment and improves glycaemic control in the majority of insulin-treated patients. Diabet Med. 2009;26(4):437–41.CrossRefGoogle Scholar
  63. Shields BM, et al. Maturity-onset diabetes of the young (MODY): how many cases are we missing? Diabetologia. 2010;53(12):2504–8.CrossRefGoogle Scholar
  64. Shields BM, et al. The development and validation of a clinical prediction model to determine the probability of MODY in patients with young-onset diabetes. Diabetologia. 2012;55(5):1265–72.CrossRefGoogle Scholar
  65. Shields BM, 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(8):1017–25.CrossRefGoogle Scholar
  66. Smith SB, et al. Rfx6 directs islet formation and insulin production in mice and humans. Nature. 2010;463(7282):775–80.CrossRefGoogle Scholar
  67. Spyer G, et al. Pregnancy outcome in patients with raised blood glucose due to a heterozygous glucokinase gene mutation. Diabet Med. 2009;26(1):14–8.CrossRefGoogle Scholar
  68. Steele AM, 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(6):e65326.CrossRefGoogle Scholar
  69. Steele AM, et al. Prevalence of vascular complications among patients with glucokinase mutations and prolonged, mild hyperglycemia. JAMA. 2014;311(3):279–86.CrossRefGoogle Scholar
  70. Stoffers DA, et al. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet. 1997;15:106–10.CrossRefGoogle Scholar
  71. Stoy J, et al. Insulin gene mutations as a cause of permanent neonatal diabetes. Proc Natl Acad Sci U S A. 2007;104(38):15040–4.CrossRefGoogle Scholar
  72. Stride A, et al. Glycosuria at 2 h post OGTT: a screening tool for unaffected subjects in families with HNF-1a mutations. Diabet Med. 2002;19(S2):59–60.Google Scholar
  73. Stride A, et al. Cross-sectional and longitudinal studies suggest pharmacological treatment used in patients with glucokinase mutations does not alter glycaemia. Diabetologia. 2014;57(1):54–6.CrossRefGoogle Scholar
  74. Szopa M, et al. A family with the Arg103Pro mutation in the NEUROD1 gene detected by next-generation sequencing – clinical characteristics of mutation carriers. Eur J Med Genet. 2016;59(2):75–9.CrossRefGoogle Scholar
  75. Tattersall RB. Mild familial diabetes with dominant inheritance. Q J Med. 1974;43:339–57.PubMedGoogle Scholar
  76. Temple IK, Shield JP. Transient neonatal diabetes, a disorder of imprinting. J Med Genet. 2002;39(12):872–5.CrossRefGoogle Scholar
  77. Thanabalasingham G, et al. A large multi-centre European study validates high-sensitivity C-reactive protein (hsCRP) as a clinical biomarker for the diagnosis of diabetes subtypes. Diabetologia. 2011;54(11):2801–10.CrossRefGoogle Scholar
  78. Thanabalasingham G, 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(6):1206–12.CrossRefGoogle Scholar
  79. Thanabalasingham G, et al. Mutations in HNF1A result in marked alterations of plasma glycan profile. Diabetes. 2013;62(4):1329–37.CrossRefGoogle Scholar
  80. Transferring Patients with Diabetes due to a KIR6.2 Mutation from Insulin to Sulphonylureas. 2017. Available from:
  81. Tuomi T, et al. Improved prandial glucose control with lower risk of hypoglycemia with nateglinide than with glibenclamide in patients with maturity-onset diabetes of the young type 3. Diabetes Care. 2006;29(2):189–94.CrossRefGoogle Scholar
  82. van den Ouweland JM, et al. Maternally inherited diabetes and deafness is a distinct subtype of diabetes and associates with a single point mutation in the mitochondrial tRNA(Leu(UUR)) gene. Diabetes. 1994;43(6):746–51.CrossRefGoogle Scholar
  83. Walsh R, et al. Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples. Genet Med. 2017;19(2):192–203.CrossRefGoogle Scholar
  84. Yamagata K, et al. Mutations in the hepatic nuclear factor 1 alpha gene in maturity-onset diabetes of the young (MODY3). Nature. 1996a;384:455–8.CrossRefGoogle Scholar
  85. Yamagata K, et al. Mutations in the hepatocyte nuclear factor 4 alpha gene in maturity-onset diabetes of the young (MODY1). Nature. 1996b;384:458–60.CrossRefGoogle Scholar
  86. (2017) 2. Classification and Diagnosis of Diabetes:. Diabetes Care 41 (Supplement 1):S13–S27Google Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Oxford Centre for Diabetes, Endocrinology and MetabolismUniversity of OxfordOxfordUK

Personalised recommendations