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Incomplete penetrance and variable expressivity in monogenic diabetes; a challenge but also an opportunity

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Abstract

Monogenic Forms of Diabetes (MFD) account for about 3% of all diabetes, and their accurate diagnosis often results in life-changing therapeutic reassignment for the patients. Like other Mendelian diseases, reduced penetrance and variable expressivity are often seen in several different types of MFD, where symptoms develop only in a portion of the persons who carry the pathogenic variant or vary widely in symptom severity and age of onset. This complicates diagnosis and disease management in MFD. In addition to its clinical importance, knowledge of genetic modifiers that confer penetrance and expressivity variability opens possibilities to identify protective genetic variants which may help probe the mechanisms of more common forms of diabetes and shed light in new therapeutic strategies. In this review, we will mainly address penetrance and expressivity variation in different types of MFD, factors that confer such variations and opportunities that come with such knowledge. Related literature was searched in PubMed, Medline and Embase. Papers with publication year from 1974 to 2023 are included. Data are either sourced from literatures or from OMIM, Clinvar and 1000 genome browser.

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Abbreviations

MFD:

Monogenic forms of diabetes

MODY:

Maturity-onset diabetes of the young

NDM:

Neonatal diabetes mellitus

T1D:

Type 1 diabetes

T2D:

Type 2 diabetes

LADA:

Latent Autoimmune Diabetes in Adults

T1DGC:

Type 1 Diabetes Genetics Consortium

References

  1. Zhang H, et al. Monogenic diabetes: a gateway to precision medicine in diabetes. J Clin Invest. 2021;131(3). https://doi.org/10.1172/JCI142244.

  2. Shi D, et al. Genetic syndromes with diabetes: a systematic review. Obes Rev. 2021;22(9). https://doi.org/10.1111/obr.13303. e13303.

  3. Sousa M, Rego T, Armas JB. Insights into the Genetics and Signaling Pathways in Maturity-Onset diabetes of the Young. Int J Mol Sci. 2022;23(21). https://doi.org/10.3390/ijms232112910.

  4. Lemelman MB, Letourneau L, Greeley SAW. Neonatal diabetes Mellitus: an update on diagnosis and management. Clin Perinatol. 2018;45(1):41–59. https://doi.org/10.1016/j.clp.2017.10.006.

    Article  PubMed  Google Scholar 

  5. Yan J, et al. Whole-exome sequencing identifies a novel INS mutation causative of maturity-onset diabetes of the young 10. J Mol Cell Biol. 2017;9(5):376–83. https://doi.org/10.1093/jmcb/mjx039.

    Article  CAS  PubMed  Google Scholar 

  6. Vesterhus M, et al. Pancreatic function in carboxyl-ester lipase knockout mice. Pancreatology. 2010;10(4):467–76. https://doi.org/10.1159/000266284.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Johansson BB, et al. Diabetes and pancreatic exocrine dysfunction due to mutations in the carboxyl ester lipase gene-maturity onset diabetes of the young (CEL-MODY): a protein misfolding disease. J Biol Chem. 2011;286(40):34593–605. https://doi.org/10.1074/jbc.M111.222679.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Morikawa S, et al. Loss of function of WFS1 causes ER stress-mediated inflammation in pancreatic Beta-cells. Front Endocrinol (Lausanne). 2022;13:849204. https://doi.org/10.3389/fendo.2022.849204.

    Article  PubMed  Google Scholar 

  9. Baltimore M. Online Mendelian Inheritance in Man, OMIM®: OMIM Entry Statistics Available online: https://www.omim.org/statistics/entry. (accessed on 14 April 2021).

  10. Valdez R, Ouyang L, Bolen J. Public Health and Rare Diseases: Oxymoron No more. Prev Chronic Dis. 2016;13:E05. https://doi.org/10.5888/pcd13.150491.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Chen R, et al. Analysis of 589,306 genomes identifies individuals resilient to severe mendelian childhood diseases. Nat Biotechnol. 2016;34(5):531–8. https://doi.org/10.1038/nbt.3514.

    Article  CAS  PubMed  Google Scholar 

  12. Kingdom R, Wright CF. Incomplete penetrance and variable expressivity: from Clinical Studies to Population cohorts. Front Genet. 2022;13:920390. https://doi.org/10.3389/fgene.2022.920390.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Li M, et al. High prevalence of a monogenic cause in Han Chinese Diagnosed with type 1 diabetes, partly driven by nonsyndromic recessive WFS1 mutations. Diabetes. 2020;69(1):121–6. https://doi.org/10.2337/db19-0510.

    Article  CAS  PubMed  Google Scholar 

  14. Marchand L, et al. Monogenic causes in the type 1 diabetes Genetics Consortium Cohort: low genetic risk for autoimmunity in Case Selection. J Clin Endocrinol Metab. 2021;106(6):1804–10. https://doi.org/10.1210/clinem/dgab056.

    Article  PubMed  PubMed Central  Google Scholar 

  15. 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. https://doi.org/10.1038/ng.2794.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Mirshahi UL, et al. Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts. Am J Hum Genet. 2022;109(11):2018–28. https://doi.org/10.1016/j.ajhg.2022.09.014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Chakera AJ, et al. The 0.1% of the population with glucokinase monogenic diabetes can be recognized by clinical characteristics in pregnancy: the Atlantic diabetes in pregnancy cohort. Diabetes Care. 2014;37(5):1230–6. https://doi.org/10.2337/dc13-2248.

    Article  CAS  PubMed  Google Scholar 

  18. Steele AM, et al. Prevalence of vascular complications among patients with glucokinase mutations and prolonged, mild hyperglycemia. JAMA. 2014;311(3):279–86. https://doi.org/10.1001/jama.2013.283980.

    Article  CAS  PubMed  Google Scholar 

  19. Goodrich JK, et al. Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes. Nat Commun. 2021;12(1):3505. https://doi.org/10.1038/s41467-021-23556-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Timsit J, et al. Searching for Maturity-Onset diabetes of the Young (MODY): when and what for? Can J Diabetes. 2016;40(5):455–61. https://doi.org/10.1016/j.jcjd.2015.12.005.

    Article  PubMed  Google Scholar 

  21. Laver TW, et al. The common p.R114W HNF4A mutation causes a distinct clinical subtype of monogenic diabetes. Diabetes. 2016;65(10):3212–7. https://doi.org/10.2337/db16-0628.

    Article  CAS  PubMed  Google Scholar 

  22. Wright CF, et al. Assessing the pathogenicity, Penetrance, and expressivity of putative disease-causing variants in a Population setting. Am J Hum Genet. 2019;104(2):275–86. https://doi.org/10.1016/j.ajhg.2018.12.015.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kettunen JLT, et al. A multigenerational study on phenotypic consequences of the most common causal variant of HNF1A-MODY. Diabetologia. 2022;65(4):632–43. https://doi.org/10.1007/s00125-021-05631-z.

    Article  CAS  PubMed  Google Scholar 

  24. Bellanne-Chantelot C, 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(2):503–8. https://doi.org/10.2337/db07-0859.

    Article  CAS  PubMed  Google Scholar 

  25. Chen YZ, 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(22):3326–33.

    CAS  PubMed  Google Scholar 

  26. Pearson ER, et al. Contrasting diabetes phenotypes associated with hepatocyte nuclear factor-1alpha and – 1beta mutations. Diabetes Care. 2004;27(5):1102–7. https://doi.org/10.2337/diacare.27.5.1102.

    Article  CAS  PubMed  Google Scholar 

  27. Horikawa Y. Maturity-onset diabetes of the young as a model for elucidating the multifactorial origin of type 2 diabetes mellitus. J Diabetes Investig. 2018;9(4):704–12. https://doi.org/10.1111/jdi.12812.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Horikawa Y, Enya M. Genetic dissection and clinical features of MODY6 (NEUROD1-MODY). Curr Diab Rep. 2019;19(3). ARTN 12.

  29. 1007/s11892-019-1130-9.

  30. Liu M et al. Loss of BETA2/NeuroD leads to malformation of the dentate gyrus and epilepsy Proc Natl Acad Sci U S A, 2000. 97(2): p. 865 – 70.DOI: https://doi.org/10.1073/pnas.97.2.865.

  31. Huang HP, et al. Neogenesis of beta-cells in adult BETA2/NeuroD-deficient mice. Mol Endocrinol. 2002;16(3):541–51. https://doi.org/10.1210/me.16.3.541.

    Article  CAS  PubMed  Google Scholar 

  32. Ushijima K, et al. KLF11 variant in a family clinically diagnosed with early childhood-onset type 1B diabetes. Pediatr Diabetes. 2019;20(6):712–9. https://doi.org/10.1111/pedi.12868.

    Article  CAS  PubMed  Google Scholar 

  33. Hildebrand JM, et al. A family harboring an MLKL loss of function variant implicates impaired necroptosis in diabetes. Cell Death Dis. 2021;12(4):345. https://doi.org/10.1038/s41419-021-03636-5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Torsvik J, et al. Mutations in the VNTR of the carboxyl-ester lipase gene (CEL) are a rare cause of monogenic diabetes. Hum Genet. 2010;127(1):55–64. https://doi.org/10.1007/s00439-009-0740-8.

    Article  CAS  PubMed  Google Scholar 

  35. Dusatkova L, et al. Frameshift mutations in the insulin gene leading to prolonged molecule of insulin in two families with maturity-onset diabetes of the Young. Eur J Med Genet. 2015;58(4):230–4. https://doi.org/10.1016/j.ejmg.2015.02.004.

    Article  PubMed  Google Scholar 

  36. Klee P, et al. A novel ABCC8 mutation illustrates the variability of the diabetes phenotypes associated with a single mutation. Diabetes Metab. 2012;38(2):179–82. https://doi.org/10.1016/j.diabet.2011.12.001.

    Article  CAS  PubMed  Google Scholar 

  37. Lenfant C, et al. Juvenile-onset diabetes and congenital cataract: “Double-Gene” mutations mimicking a syndromic diabetes presentation. Genes (Basel). 2017;8(11). https://doi.org/10.3390/genes8110309.

  38. Bonnefond A, et al. Whole-exome sequencing and high throughput genotyping identified KCNJ11 as the thirteenth MODY gene. PLoS ONE. 2012;7(6):e37423. https://doi.org/10.1371/journal.pone.0037423.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sansbury FH, et al. Biallelic RFX6 mutations can cause childhood as well as neonatal onset diabetes mellitus. Eur J Hum Genet. 2015;23(12):1744–8. https://doi.org/10.1038/ejhg.2015.161.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yorifuji T, et al. Abnormalities in chromosome 6q24 as a cause of early-onset, non-obese, non-autoimmune diabetes mellitus without history of neonatal diabetes. Diabet Med. 2015;32(7):963–7. https://doi.org/10.1111/dme.12758.

    Article  CAS  PubMed  Google Scholar 

  41. 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. https://doi.org/10.1073/pnas.0707291104.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Yorifuji T, et al. The C42R mutation in the Kir6.2 (KCNJ11) gene as a cause of transient neonatal diabetes, childhood diabetes, or later-onset, apparently type 2 diabetes mellitus. J Clin Endocrinol Metab. 2005;90(6):3174–8. https://doi.org/10.1210/jc.2005-0096.

    Article  CAS  PubMed  Google Scholar 

  43. De Franco E, et al. Dominant ER stress-inducing WFS1 mutations underlie a genetic syndrome of Neonatal/Infancy-Onset diabetes, congenital Sensorineural Deafness, and congenital cataracts. Diabetes. 2017;66(7):2044–53. https://doi.org/10.2337/db16-1296.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Matsunaga K, et al. Wolfram syndrome in the japanese population; molecular analysis of WFS1 gene and characterization of clinical features. PLoS ONE. 2014;9(9):e106906. https://doi.org/10.1371/journal.pone.0106906.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Horikawa Y, et al. NEUROD1-deficient diabetes (MODY6): identification of the first cases in japanese and the clinical features. Pediatr Diabetes. 2018;19(2):236–42. https://doi.org/10.1111/pedi.12553.

    Article  CAS  PubMed  Google Scholar 

  46. Kristinsson SY, et al. MODY in Iceland is associated with mutations in HNF-1alpha and a novel mutation in NeuroD1. Diabetologia. 2001;44(11):2098–103. https://doi.org/10.1007/s001250100016.

    Article  CAS  PubMed  Google Scholar 

  47. 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. https://doi.org/10.1016/j.ejmg.2016.01.002.

    Article  PubMed  Google Scholar 

  48. Stride A, et al. Intrauterine hyperglycemia is associated with an earlier diagnosis of diabetes in HNF-1alpha gene mutation carriers. Diabetes Care. 2002;25(12):2287–91. https://doi.org/10.2337/diacare.25.12.2287.

    Article  CAS  PubMed  Google Scholar 

  49. Horikawa Y, et al. Screening of diabetes of youth for hepatocyte nuclear factor 1 mutations: clinical phenotype of HNF1beta-related maturity-onset diabetes of the young and HNF1alpha-related maturity-onset diabetes of the young in japanese. Diabet Med. 2014;31(6):721–7. https://doi.org/10.1111/dme.12416.

    Article  CAS  PubMed  Google Scholar 

  50. Locke JM, et al. The common HNF1A variant I27L is a modifier of age at diabetes diagnosis in individuals with HNF1A-MODY. Diabetes. 2018;67(9):1903–7. https://doi.org/10.2337/db18-0133.

    Article  CAS  PubMed  Google Scholar 

  51. Forlani G, et al. Double heterozygous mutations involving both HNF1A/MODY3 and HNF4A/MODY1 genes. Diabetes Care. 2010;33(11):2336–8. https://doi.org/10.2337/dc10-0561.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Shankar RK, et al. Digenic heterozygous HNF1A and HNF4A mutations in two siblings with childhood-onset diabetes. Pediatr Diabetes. 2013;14(7):535–8. https://doi.org/10.1111/pedi.12018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Cervin C, et al. Cosegregation of MIDD and MODY in a pedigree: functional and clinical consequences. Diabetes. 2004;53(7):1894–9. https://doi.org/10.2337/diabetes.53.7.1894.

    Article  CAS  PubMed  Google Scholar 

  54. Bennett JT, et al. Molecular genetic testing of patients with monogenic diabetes and hyperinsulinism. Mol Genet Metab. 2015;114(3):451–8. https://doi.org/10.1016/j.ymgme.2014.12.304.

    Article  CAS  PubMed  Google Scholar 

  55. Yang Y, Chan L. Monogenic diabetes: what it teaches us on the common forms of type 1 and type 2 diabetes. Endocr Rev. 2016;37(3):190–222. https://doi.org/10.1210/er.2015-1116.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Tattersall RB. Mild familial diabetes with dominant inheritance. Q J Med. 1974;43(170):339–57.

    CAS  PubMed  Google Scholar 

  57. Peixoto-Barbosa R, Reis AF, Giuffrida FMA. Update on clinical screening of maturity-onset diabetes of the young (MODY). Diabetol Metab Syndr. 2020;12:50. https://doi.org/10.1186/s13098-020-00557-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Misra S, et al. South asian individuals with diabetes who are referred for MODY testing in the UK have a lower mutation pick-up rate than white european people. Diabetologia. 2016;59(10):2262–5. https://doi.org/10.1007/s00125-016-4056-7.

    Article  PubMed  PubMed Central  Google Scholar 

  59. DiMeglio LA, Evans-Molina C, Oram RA. Type 1 diabetes. Lancet. 2018;391(10138):2449–62. https://doi.org/10.1016/S0140-6736(18)31320-5.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Parkkola A et al. Extended family history of type 1 diabetes and phenotype and genotype of newly diagnosed children Diabetes Care, 2013. 36(2): p. 348 – 54.DOI: https://doi.org/10.2337/dc12-0445.

  61. Bansal V, et al. Spectrum of mutations in monogenic diabetes genes identified from high-throughput DNA sequencing of 6888 individuals. BMC Med. 2017;15(1):213. https://doi.org/10.1186/s12916-017-0977-3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Anik A, et al. Maturity-onset diabetes of the young (MODY): an update. J Pediatr Endocrinol Metab. 2015;28(3–4):251–63. https://doi.org/10.1515/jpem-2014-0384.

    Article  CAS  PubMed  Google Scholar 

  63. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Ostoft SH, et al. Glucose-lowering effects and low risk of hypoglycemia in patients with maturity-onset diabetes of the young when treated with a GLP-1 receptor agonist: a double-blind, randomized, crossover trial. Diabetes Care. 2014;37(7):1797–805. https://doi.org/10.2337/dc13-3007.

    Article  CAS  PubMed  Google Scholar 

  65. Kim GL, Kwak SH, Yu J. A case of monogenic diabetes mellitus caused by a novel heterozygous RFX6 nonsense mutation in a 14-year-old girl. J Pediatr Endocrinol Metab. 2021;34(12):1619–22. https://doi.org/10.1515/jpem-2021-0275.

    Article  PubMed  Google Scholar 

  66. Toppings NB et al. Wolfram Syndrome: A Case Report and Review of Clinical Manifestations, Genetics Pathophysiology, and Potential Therapies Case Rep Endocrinol, 2018. 2018: p. 9412676.DOI: https://doi.org/10.1155/2018/9412676.

  67. Frontino G, et al. Case Report: off-label Liraglutide Use in Children with Wolfram Syndrome Type 1: extensive characterization of four patients. Front Pediatr. 2021;9:755365. https://doi.org/10.3389/fped.2021.755365.

    Article  PubMed  PubMed Central  Google Scholar 

  68. Danielpur L, et al. GLP-1-RA corrects mitochondrial Labile Iron Accumulation and improves beta-cell function in type 2 Wolfram Syndrome. J Clin Endocrinol Metab. 2016;101(10):3592–9. https://doi.org/10.1210/jc.2016-2240.

    Article  CAS  PubMed  Google Scholar 

  69. Gallwitz B. Novel therapeutic approaches in diabetes. Endocr Dev. 2016;31:43–56. https://doi.org/10.1159/000439372.

    Article  CAS  PubMed  Google Scholar 

  70. Naya FJ, et al. Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/neuroD-deficient mice. Genes Dev. 1997;11(18):2323–34. https://doi.org/10.1101/gad.11.18.2323.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Huang HP et al. Neogenesis of beta-cells in adult BETA2/NeuroD-deficient mice Mol Endocrinol, 2002. 16(3): p. 541 – 51.DOI: https://doi.org/10.1210/mend.16.3.0784.

  72. Garcia-Gonzalez MA, et al. A suppressor locus for MODY3-diabetes. Sci Rep. 2016;6:33087. https://doi.org/10.1038/srep33087.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. 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. https://doi.org/10.1007/s00125-016-4167-1.

    Article  CAS  PubMed  Google Scholar 

  74. Broome DT, et al. Approach to the patient with MODY-Monogenic diabetes. J Clin Endocrinol Metab. 2021;106(1):237–50. https://doi.org/10.1210/clinem/dgaa710.

    Article  PubMed  Google Scholar 

  75. Faguer S et al. Diagnosis, management, and prognosis of HNF1B nephropathy in adulthood Kidney Int, 2011. 80(7): p. 768 – 76.DOI: https://doi.org/10.1038/ki.2011.225.

  76. Horikawa Y. Maturity-onset diabetes of the young as a model for elucidating the multifactorial origin of type 2 diabetes mellitus. J Diabetes Invest. 2018;9(4):704–12. https://doi.org/10.1111/jdi.12812.

    Article  CAS  Google Scholar 

  77. Horikawa Y, Enya M. Genetic dissection and clinical features of MODY6 (NEUROD1-MODY). Curr Diab Rep. 2019;19(3):12. https://doi.org/10.1007/s11892-019-1130-9.

    Article  PubMed  Google Scholar 

  78. Demirbilek H, et al. Permanent neonatal diabetes mellitus and neurological abnormalities due to a novel homozygous missense mutation in NEUROD1. Pediatr Diabetes. 2018;19(5):898–904. https://doi.org/10.1111/pedi.12669.

    Article  CAS  PubMed  Google Scholar 

  79. 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. https://doi.org/10.1038/ng1708.

    Article  CAS  PubMed  Google Scholar 

  80. Raeder H, et al. Absence of diabetes and pancreatic exocrine dysfunction in a transgenic model of carboxyl-ester lipase-MODY (maturity-onset diabetes of the young). PLoS ONE. 2013;8(4):e60229. https://doi.org/10.1371/journal.pone.0060229.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Johnson SR, et al. A novel INS mutation in a family with maturity-onset diabetes of the young: variable insulin secretion and putative mechanisms. Pediatr Diabetes. 2018;19(5):905–9. https://doi.org/10.1111/pedi.12679.

    Article  CAS  PubMed  Google Scholar 

  82. Laurenzano SE, et al. Neonatal diabetes mellitus due to a novel variant in the INS gene. Cold Spring Harb Mol Case Stud. 2019;5(4). https://doi.org/10.1101/mcs.a004085.

  83. Reilly F, et al. Phenotype, genotype and glycaemic variability in people with activating mutations in the ABCC8 gene: response to appropriate therapy. Diabet Med. 2020;37(5):876–84. https://doi.org/10.1111/dme.14145.

    Article  CAS  PubMed  Google Scholar 

  84. Patel KA, et al. Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance. Nat Commun. 2017;8(1):888. https://doi.org/10.1038/s41467-017-00895-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Laver TW, et al. Evaluation of evidence for pathogenicity demonstrates that BLK, KLF11, and PAX4 should not be included in Diagnostic Testing for MODY. Diabetes. 2022;71(5):1128–36. https://doi.org/10.2337/db21-0844.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Owen KR. Monogenic diabetes in adults: what are the new developments? Curr Opin Genet Dev. 2018;50:103–10. https://doi.org/10.1016/j.gde.2018.04.006.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The study was supported by Grants from the Nature Science Foundation of Guangdong Province, China (2020A1515110660, 2021A1515010884), Science and Technology Planning Project of Guangdong Province, China (mmkj2020025) and China Postdoctoral Science Foundation (2021M691235); MaiDa Gene Technology is indebted to the 5313 Leading Talents Project of Zhoushan city, Zhejiang province for partial funding support of this project.

Funding

Meihang Li is a stock holder and Constantin Polychronakos is the Chief Scientific Officer of Zhejiang MaiDa Gene Tech Co. Ltd. This company is a publicly funded for-profit corporation that will be offering genetic testing services.

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Authors and Affiliations

  1. College of pharmacy, Jinan University, 601 Huangpu Avenue West, Guangzhou, Guangdong, China

    Meihang Li & Ying Wang

  2. Department of Emergency, Department of Endorinology, Maoming People’s Hospital, 101 Weimin Road, Maoming, Guangdong, China

    Meihang Li & Chunbo Chen

  3. Montreal Children’s Hospital and the Endocrine Genetics Laboratory, Child Health and Human Development Program, Research Institute of the McGill University Health Centre, Montreal, China

    Meihang Li, Natalija Popovic & Constantin Polychronakos

  4. MaiDa Gene Technology, Zhoushan, China

    Meihang Li & Constantin Polychronakos

  5. Department of Critical Care Medicine, Shenzhen People’s Hospital, The Second Clinical Medical College of Jinan University, The First Affiliated Hospital of South University of Science and Technology, Shenzhen, China

    Chunbo Chen

  6. Department of Intensive Care Unit of Cardiovascular Surgery, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China

    Chunbo Chen

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Li, M., Popovic, N., Wang, Y. et al. Incomplete penetrance and variable expressivity in monogenic diabetes; a challenge but also an opportunity. Rev Endocr Metab Disord 24, 673–684 (2023). https://doi.org/10.1007/s11154-023-09809-1

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