Abstract
Monogenic diabetes includes several clinical conditions generally characterized by early-onset diabetes, such as neonatal diabetes, maturity-onset diabetes of the young (MODY) and various diabetes-associated syndromes. However, patients with apparent type 2 diabetes mellitus may actually have monogenic diabetes. Indeed, the same monogenic diabetes gene can contribute to different forms of diabetes with early or late onset, depending on the functional impact of the variant, and the same pathogenic variant can produce variable diabetes phenotypes, even in the same family. Monogenic diabetes is mostly caused by impaired function or development of pancreatic islets, with defective insulin secretion in the absence of obesity. The most prevalent form of monogenic diabetes is MODY, which may account for 0.5–5% of patients diagnosed with non-autoimmune diabetes but is probably underdiagnosed owing to insufficient genetic testing. Most patients with neonatal diabetes or MODY have autosomal dominant diabetes. More than 40 subtypes of monogenic diabetes have been identified to date, the most prevalent being deficiencies of GCK and HNF1A. Precision medicine approaches (including specific treatments for hyperglycaemia, monitoring associated extra-pancreatic phenotypes and/or following up clinical trajectories, especially during pregnancy) are available for some forms of monogenic diabetes (including GCK- and HNF1A-diabetes) and increase patients’ quality of life. Next-generation sequencing has made genetic diagnosis affordable, enabling effective genomic medicine in monogenic diabetes.
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Acknowledgements
A.B. is supported by the European Research Council (ERC OπO: 101043671). A.B., M.V. and P.F. are supported by the National Center for Precision Diabetic Medicine — PreciDIAB, which is jointly supported by the French National Agency for Research (ANR-18-IBHU-0001), by the European Union (FEDER), by the Hauts-de-France Regional Council and by the European Metropolis of Lille (MEL). V.M. and R.U. acknowledge the support of M/S Servier Laboratories to their work on monogenic diabetes as part of the PAN INDIA STUDY ON MODY (CTRI/2019/12/022394 & CTRI/2020/03/023968).
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Introduction (A.B. and M.V.); Epidemiology (P.F.); Mechanisms/pathophysiology (A.B., A.D., M.V. and R.N.K.); Diagnosis, screening and prevention (A.B., R.U., V.M. and V.T.); Management (P.F., V.M. and V.T.); Quality of life (P.F. and A.B.); Outlook (P.F.); Overview of Primer (A.B. and P.F.).
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Nature Reviews Disease Primers thanks L. Billings, K. Owen and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
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ClinGen Monogenic Diabetes Variant Curation Expert Panel: https://clinicalgenome.org/affiliation/50016/
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Bonnefond, A., Unnikrishnan, R., Doria, A. et al. Monogenic diabetes. Nat Rev Dis Primers 9, 12 (2023). https://doi.org/10.1038/s41572-023-00421-w
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DOI: https://doi.org/10.1038/s41572-023-00421-w
