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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Riddle, M. C. et al. Monogenic diabetes: from genetic insights to population-based precision in care. reflections from a diabetes care editors’ expert forum. Diabetes Care 43, 3117–3128 (2020).
Froguel, P. et al. Close linkage of glucokinase locus on chromosome 7p to early-onset non-insulin-dependent diabetes mellitus. Nature 356, 162–164 (1992).
Vionnet, N. et al. Nonsense mutation in the glucokinase gene causes early-onset non-insulin-dependent diabetes mellitus. Nature 356, 721–722 (1992). Study identifying pathogenic mutations in GCK as leading to one of the most prevalent forms of monogenic diabetes.
American Diabetes Association Professional Practice Committee. 2. Classification and diagnosis of diabetes: standards of medical care in diabetes — 2022. Diabetes Care 45 (Suppl. 1), S17–S38 (2022).
Bonnefond, A. et al. Pathogenic variants in actionable MODY genes are associated with type 2 diabetes. Nat. Metab. 2, 1126–1134 (2020). A study that highlights the incomplete penetrance of pathogenic mutations in monogenic diabetes genes, which are even found in patients with suspected typical T2DM.
Ahlqvist, E. et al. Novel subgroups of adult-onset diabetes and their association with outcomes: a data-driven cluster analysis of six variables. Lancet Diabetes Endocrinol. 6, 361–369 (2018).
Bonnefond, A. & Froguel, P. Clustering for a better prediction of type 2 diabetes mellitus. Nat. Rev. Endocrinol. 17, 193–194 (2021).
Yang, Y. & Chan, L. Monogenic diabetes: what it teaches us on the common forms of type 1 and type 2 diabetes. Endocr. Rev. 37, 190–222 (2016).
Vaxillaire, M., Froguel, P. & Bonnefond, A. How recent advances in genomics improve precision diagnosis and personalized care of maturity-onset diabetes of the young. Curr. Diabetes Rep. 19, 79 (2019).
Shields, B. M. et al. Maturity-onset diabetes of the young (MODY): how many cases are we missing? Diabetologia 53, 2504–2508 (2010).
Donath, X. et al. Next-generation sequencing identifies monogenic diabetes in 16% of patients with late adolescence/adult-onset diabetes selected on a clinical basis: a cross-sectional analysis. BMC Med. 17, 132 (2019).
Vaxillaire, M. et al. Monogenic diabetes characteristics in a transnational multicenter study from Mediterranean countries. Diabetes Res. Clin. Pract. 171, 108553 (2021).
Mohan, V. et al. Comprehensive genomic analysis identifies pathogenic variants in maturity-onset diabetes of the young (MODY) patients in South India. BMC Med. Genet. 19, 22 (2018).
Park, S. S. et al. Identifying pathogenic variants of monogenic diabetes using targeted panel sequencing in an East Asian population. J. Clin. Endocrinol. Metab. https://doi.org/10.1210/jc.2018-02397 (2019).
Breidbart, E. et al. Frequency and characterization of mutations in genes in a large cohort of patients referred to MODY registry. J. Pediatr. Endocrinol. Metab. 34, 633–638 (2021).
Pezzilli, S. et al. Pathogenic variants of MODY-genes in adult patients with early-onset type 2 diabetes. Acta Diabetol. 59, 747–750 (2022).
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. 45, 1380–1385 (2013).
Mirshahi, U. L. et al. Reduced penetrance of MODY-associated HNF1A/HNF4A variants but not GCK variants in clinically unselected cohorts. Am. J. Hum. Genet. 109, 2018–2028 (2022).
Da Silva Xavier, G. The cells of the islets of Langerhans. J. Clin. Med. 7, E54 (2018).
Yamagata, K. et al. Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young (MODY3). Nature 384, 455–458 (1996). Study identifying pathogenic mutations in HNF1A as leading to one of the most prevalent forms of monogenic diabetes.
Yamagata, K. et al. Mutations in the hepatocyte nuclear factor-4α gene in maturity-onset diabetes of the young (MODY1). Nature 384, 458–460 (1996).
Raeder, H. et al. Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction. Nat. Genet. 38, 54–62 (2006).
Malikova, J. et al. Functional analyses of HNF1A-MODY variants refine the interpretation of identified sequence variants. J. Clin. Endocrinol. Metab. 105, dgaa051 (2020).
Li, L.-M., Jiang, B.-G. & Sun, L.-L. HNF1A: from monogenic diabetes to type 2 diabetes and gestational diabetes mellitus. Front. Endocrinol. 13, 829565 (2022).
Bonnefond, A. et al. GATA6 inactivating mutations are associated with heart defects and, inconsistently, with pancreatic agenesis and diabetes. Diabetologia 55, 2845–2847 (2012).
Jonsson, J., Carlsson, L., Edlund, T. & Edlund, H. Insulin-promoter-factor 1 is required for pancreas development in mice. Nature 371, 606–609 (1994).
Duque, M., Amorim, J. P. & Bessa, J. Ptf1a function and transcriptional cis-regulation, a cornerstone in vertebrate pancreas development. FEBS J. 289, 5121–5136 (2022).
Tiyaboonchai, A. et al. GATA6 plays an important role in the induction of human definitive endoderm, development of the pancreas, and functionality of pancreatic β cells. Stem Cell Rep. 8, 589–604 (2017).
Rouzier, C. et al. A novel CISD2 mutation associated with a classical Wolfram syndrome phenotype alters Ca2+ homeostasis and ER-mitochondria interactions. Hum. Mol. Genet. 26, 1599–1611 (2017).
Shrestha, N., De Franco, E., Arvan, P. & Cnop, M. Pathological β-cell endoplasmic reticulum stress in type 2 diabetes: current evidence. Front. Endocrinol. 12, 650158 (2021).
Graff, S. M. et al. A KCNK16 mutation causing TALK-1 gain-of-function is associated with maturity-onset diabetes of the young. JCI Insight 6, e138057 (2021).
Santer, R. et al. Mutations in GLUT2, the gene for the liver-type glucose transporter, in patients with Fanconi-Bickel syndrome. Nat. Genet. 17, 324–326 (1997).
Labay, V. et al. Mutations in SLC19A2 cause thiamine-responsive megaloblastic anaemia associated with diabetes mellitus and deafness. Nat. Genet. 22, 300–304 (1999).
Jungtrakoon, P. et al. Loss-of-function mutation in thiamine transporter 1 in a family with autosomal dominant diabetes. Diabetes 68, 1084–1093 (2019).
Mancuso, M. et al. The m.3243A>G mitochondrial DNA mutation and related phenotypes. A matter of gender? J. Neurol. 261, 504–510 (2014).
Pickett, S. J. et al. Phenotypic heterogeneity in m.3243A>G mitochondrial disease: the role of nuclear factors. Ann. Clin. Transl. Neurol. 5, 333–345 (2018).
Vaxillaire, M. & Froguel, P. Monogenic diabetes in the young, pharmacogenetics and relevance to multifactorial forms of type 2 diabetes. Endocr. Rev. 29, 254–264 (2008).
Raimondo, A. et al. Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability. Hum. Mol. Genet. 23, 6432–6440 (2014).
Rees, M. G. et al. A panel of diverse assays to interrogate the interaction between glucokinase and glucokinase regulatory protein, two vital proteins in human disease. PLoS ONE 9, e89335 (2014).
Njølstad, P. R. et al. Neonatal diabetes mellitus due to complete glucokinase deficiency. N. Engl. J. Med. 344, 1588–1592 (2001).
Meur, G. et al. Insulin gene mutations resulting in early-onset diabetes: marked differences in clinical presentation, metabolic status, and pathogenic effect through endoplasmic reticulum retention. Diabetes 59, 653–661 (2010).
Garin, I. et al. Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis. Proc. Natl Acad. Sci. USA 107, 3105–3110 (2010).
Bonnefond, A. et al. Disruption of a novel Kruppel-like transcription factor p300-regulated pathway for insulin biosynthesis revealed by studies of the c.-331 INS mutation found in neonatal diabetes mellitus. J. Biol. Chem. 286, 28414–28424 (2011).
Johansson, B. B. et al. The role of the carboxyl ester lipase (CEL) gene in pancreatic disease. Pancreatology 18, 12–19 (2018).
Kahraman, S. et al. Abnormal exocrine-endocrine cell cross-talk promotes β-cell dysfunction and loss in MODY8. Nat. Metab. 4, 76–89 (2022).
Tattersall, R. B. & Fajans, S. S. A difference between the inheritance of classical juvenile-onset and maturity-onset type diabetes of young people. Diabetes 24, 44–53 (1975).
Steele, A. M. et al. Prevalence of vascular complications among patients with glucokinase mutations and prolonged, mild hyperglycemia. JAMA 311, 279–286 (2014). A study that showed a very low prevalence of vascular complications in patients with long-term dominant GCK-diabetes.
Di Paola, R., Marucci, A. & Trischitta, V. The need to increase clinical skills and change the genetic testing strategy for monogenic diabetes. Diabetes 71, 379–380 (2022).
Zhang, H., Colclough, K., Gloyn, A. L. & Pollin, T. I. Monogenic diabetes: a gateway to precision medicine in diabetes. J. Clin. Invest. 131, 142244 (2021).
Kleinberger, J. W. et al. Monogenic diabetes in overweight and obese youth diagnosed with type 2 diabetes: the TODAY clinical trial. Genet. Med. 20, 583–590 (2018).
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 35, 1206–1212 (2012).
Flannick, J., Johansson, S. & Njølstad, P. R. Common and rare forms of diabetes mellitus: towards a continuum of diabetes subtypes. Nat. Rev. Endocrinol. 12, 394–406 (2016).
Shaw-Smith, C. et al. GATA4 mutations are a cause of neonatal and childhood-onset diabetes. Diabetes 63, 2888–2894 (2014).
Bonnefond, A. et al. Whole-exome sequencing and high throughput genotyping identified KCNJ11 as the thirteenth MODY gene. PLoS ONE 7, e37423 (2012).
Kettunen, J. L. T. et al. A multigenerational study on phenotypic consequences of the most common causal variant of HNF1A-MODY. Diabetologia 65, 632–643 (2022).
Saint-Martin, C., Bouvet, D., Bastide, M. & Bellanné-Chantelot, C. Gene panel sequencing of patients with monogenic diabetes brings to light genes typically associated with syndromic presentations. Diabetes 71, 578–584 (2022).
Colclough, K., Ellard, S., Hattersley, A. & Patel, K. Syndromic monogenic diabetes genes should be tested in patients with a clinical suspicion of maturity-onset diabetes of the young. Diabetes 71, 530–537 (2022). Saint-Martin, C. et al. and Colclough, K. et al. highlight the incomplete penetrance of pathogenetic mutations in syndromic monogenic diabetes genes; indeed, these mutations have been found in patients with suspected non-syndromic monogenic diabetes.
Patel, K. A. et al. Systematic genetic testing for recessively inherited monogenic diabetes: a cross-sectional study in paediatric diabetes clinics. Diabetologia 65, 336–342 (2022).
Bonnefond, A. & Semple, R. K. Achievements, prospects and challenges in precision care for monogenic insulin-deficient and insulin-resistant diabetes. Diabetologia 65, 1782–1795 (2022).
Chapla, A. et al. Maturity onset diabetes of the young in India – a distinctive mutation pattern identified through targeted next-generation sequencing. Clin. Endocrinol. 82, 533–542 (2015).
Shields, B. M. et al. The development and validation of a clinical prediction model to determine the probability of MODY in patients with young-onset diabetes. Diabetologia 55, 1265–1272 (2012).
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 59, 2262–2265 (2016).
Carroll, R. W. & Murphy, R. Monogenic diabetes: a diagnostic algorithm for clinicians. Genes 4, 522–535 (2013).
Rubio-Cabezas, O. & Ellard, S. Diabetes mellitus in neonates and infants: genetic heterogeneity, clinical approach to diagnosis, and therapeutic options. Horm. Res. Paediatr. 80, 137–146 (2013).
Pipatpolkai, T., Usher, S., Stansfeld, P. J. & Ashcroft, F. M. New insights into KATP channel gene mutations and neonatal diabetes mellitus. Nat. Rev. Endocrinol. 16, 378–393 (2020).
Shepherd, M. et al. Predictive genetic testing in maturity-onset diabetes of the young (MODY). Diabet. Med. 18, 417–421 (2001).
Dubois-Laforgue, D. et al. Diabetes, associated clinical spectrum, long-term prognosis, and genotype/phenotype correlations in 201 adult patients with hepatocyte nuclear factor 1B (HNF1B) molecular defects. Diabetes Care 40, 1436–1443 (2017).
Shepherd, M. et al. Systematic population screening, using biomarkers and genetic testing, identifies 2.5% of the U.K. pediatric diabetes population with monogenic diabetes. Diabetes Care 39, 1879–1888 (2016).
Shields, B. M. et al. Population-based assessment of a biomarker-based screening pathway to aid diagnosis of monogenic diabetes in young-onset patients. Diabetes Care 40, 1017–1025 (2017).
Carlsson, A. et al. Absence of islet autoantibodies and modestly raised glucose values at diabetes diagnosis should lead to testing for MODY: lessons from a 5-year pediatric swedish national cohort study. Diabetes Care 43, 82–89 (2020).
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. 98, 4055–4062 (2013).
Johnson, S. R. et al. Comprehensive genetic screening: the prevalence of maturity-onset diabetes of the young gene variants in a population-based childhood diabetes cohort. Pediatr. Diabetes 20, 57–64 (2019).
Dillon, O. J. et al. Exome sequencing has higher diagnostic yield compared to simulated disease-specific panels in children with suspected monogenic disorders. Eur. J. Hum. Genet. 26, 644–651 (2018).
Xue, Y., Ankala, A., Wilcox, W. R. & Hegde, M. R. Solving the molecular diagnostic testing conundrum for Mendelian disorders in the era of next-generation sequencing: single-gene, gene panel, or exome/genome sequencing. Genet. Med. 17, 444–451 (2015).
Montagne, L. et al. CoDE-seq, an augmented whole-exome sequencing, enables the accurate detection of CNVs and mutations in Mendelian obesity and intellectual disability. Mol. Metab. 13, 1–9 (2018).
Richards, S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 17, 405–424 (2015).
Ellard, S., Colclough, K., Patel, K. A. & Hattersley, A. T. Prediction algorithms: pitfalls in interpreting genetic variants of autosomal dominant monogenic diabetes. J. Clin. Invest. 130, 14–16 (2020).
Fajans, S. S. Heterogeneity of insulin responses in maturity-onset type diabetes (MOD) and in maturity-onset type diabetes of young people (MODY). Adv. Exp. Med. Biol. 119, 171–175 (1979).
Tattersall, R. B. & Mansell, P. I. Maturity onset-type diabetes of the young (MODY): one condition or many? Diabet. Med. 8, 402–410 (1991).
Shepherd, M. H. et al. A UK nationwide prospective study of treatment change in MODY: genetic subtype and clinical characteristics predict optimal glycaemic control after discontinuing insulin and metformin. Diabetologia 61, 2520–2527 (2018).
Timsit, J., Ciangura, C., Dubois-Laforgue, D., Saint-Martin, C. & Bellanne-Chantelot, C. Pregnancy in women with monogenic diabetes due to pathogenic variants of the glucokinase gene: lessons and challenges. Front. Endocrinol. 12, 802423 (2021).
Shields, B. M. et al. Mutations in the glucokinase gene of the fetus result in reduced placental weight. Diabetes Care 31, 753–757 (2008).
Urbanová, J., Brunerová, L., Nunes, M. & Brož, J. Identification of MODY among patients screened for gestational diabetes: a clinician’s guide. Arch. Gynecol. Obstet. 302, 305–314 (2020).
Bosselaar, M., Hattersley, A. T. & Tack, C. J. J. High sensitivity to sulphonylurea treatment in 2 patients with maturity-onset diabetes of the young type 3. Ned. Tijdschr. Geneeskd. 146, 726–729 (2002).
Stankute, I. et al. Systematic genetic study of youth with diabetes in a single country reveals the prevalence of diabetes subtypes, novel candidate genes, and response to precision therapy. Diabetes 69, 1065 (2020).
Broome, D. T., Tekin, Z., Pantalone, K. M. & Mehta, A. E. Novel use of GLP-1 receptor agonist therapy in HNF4A-MODY. Diabetes Care 43, e65 (2020).
Haddouche, A. et al. Liver adenomatosis in patients with hepatocyte nuclear factor-1 alpha maturity onset diabetes of the young (HNF1A-MODY): clinical, radiological and pathological characteristics in a French series. J. Diabetes 12, 48–57 (2020).
Bowman, P. et al. Effectiveness and safety of long-term treatment with sulfonylureas in patients with neonatal diabetes due to KCNJ11 mutations: an international cohort study. Lancet Diabetes Endocrinol. 6, 637–646 (2018).
Iafusco, D. et al. No beta cell desensitisation after a median of 68 months on glibenclamide therapy in patients with KCNJ11-associated permanent neonatal diabetes. Diabetologia 54, 2736–2738 (2011).
Babiker, T. et al. Successful transfer to sulfonylureas in KCNJ11 neonatal diabetes is determined by the mutation and duration of diabetes. Diabetologia 59, 1162–1166 (2016).
de Gouveia Buff Passone, C. et al. Sulfonylurea for improving neurological features in neonatal diabetes: a systematic review and meta-analyses. Pediatr. Diabetes 23, 675–692 (2022).
Aarthy, R. et al. Clinical features, complications and treatment of rarer forms of maturity-onset diabetes of the young (MODY) - a review. J. Diabetes Complicat. 35, 107640 (2021).
Urakami, T. Maturity-onset diabetes of the young (MODY): current perspectives on diagnosis and treatment. Diabetes Metab. Syndr. Obes. 12, 1047–1056 (2019).
Asif, M. The prevention and control the type-2 diabetes by changing lifestyle and dietary pattern. J. Educ. Health Promot. 3, 1 (2014).
Naylor, R. N. et al. Cost-effectiveness of MODY genetic testing: translating genomic advances into practical health applications. Diabetes Care 37, 202–209 (2014).
Greeley, S. A. W. et al. The cost-effectiveness of personalized genetic medicine: the case of genetic testing in neonatal diabetes. Diabetes Care 34, 622–627 (2011).
GoodSmith, M. S., Skandari, M. R., Huang, E. S. & Naylor, R. N. The impact of biomarker screening and cascade genetic testing on the cost-effectiveness of MODY genetic testing. Diabetes Care 42, 2247–2255 (2019).
Pasquali, L. et al. Pancreatic islet enhancer clusters enriched in type 2 diabetes risk-associated variants. Nat. Genet. 46, 136–143 (2014).
Gaulton, K. J. et al. Genetic fine mapping and genomic annotation defines causal mechanisms at type 2 diabetes susceptibility loci. Nat. Genet. 47, 1415–1425 (2015).
Ndiaye, F. K. et al. Expression and functional assessment of candidate type 2 diabetes susceptibility genes identify four new genes contributing to human insulin secretion. Mol. Metab. 6, 459–470 (2017).
Khera, A. V. et al. Genome-wide polygenic scores for common diseases identify individuals with risk equivalent to monogenic mutations. Nat. Genet. 50, 1219–1224 (2018).
Weedon, M. N. et al. Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis. Nat. Genet. 46, 61–64 (2014).
Rees, M. G. & Gloyn, A. L. Small molecular glucokinase activators: has another new anti-diabetic therapeutic lost favour? Br. J. Pharmacol. 168, 335–338 (2013).
Sharma, P. et al. Targeting human Glucokinase for the treatment of type 2 diabetes: an overview of allosteric Glucokinase activators. J. Diabetes Metab. Disord. 21, 1129–1137 (2022).
Stoffers, D. A., Ferrer, J., Clarke, W. L. & Habener, J. F. Early-onset type-II diabetes mellitus (MODY4) linked to IPF1. Nat. Genet. 17, 138–139 (1997).
Horikawa, Y. et al. Mutation in hepatocyte nuclear factor-1 beta gene (TCF2) associated with MODY. Nat. Genet. 17, 384–385 (1997).
Malecki, M. T. et al. Mutations in NEUROD1 are associated with the development of type 2 diabetes mellitus. Nat. Genet. 23, 323–328 (1999).
Bowman, P. et al. Heterozygous ABCC8 mutations are a cause of MODY. Diabetologia 55, 123–127 (2012).
Bonnycastle, L. L. et al. Autosomal dominant diabetes arising from a Wolfram syndrome 1 mutation. Diabetes 62, 3943–3950 (2013).
Igoillo-Esteve, M. et al. tRNA methyltransferase homolog gene TRMT10A mutation in young onset diabetes and primary microcephaly in humans. PLoS Genet. 9, e1003888 (2013).
Simaite, D. et al. Recessive mutations in PCBD1 cause a new type of early-onset diabetes. Diabetes 63, 3557–3564 (2014).
Prudente, S. et al. Loss-of-function mutations in APPL1 in familial diabetes mellitus. Am. J. Hum. Genet. 97, 177–185 (2015).
Patel, K. A. et al. Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance. Nat. Commun. 8, 888 (2017).
Iacovazzo, D. et al. MAFA missense mutation causes familial insulinomatosis and diabetes mellitus. Proc. Natl Acad. Sci. USA 115, 1027–1032 (2018).
Philippi, A. et al. Mutations and variants of ONECUT1 in diabetes. Nat. Med. 27, 1928–1940 (2021).
Yorifuji, T. et al. Neonatal diabetes mellitus and neonatal polycystic, dysplastic kidneys: phenotypically discordant recurrence of a mutation in the hepatocyte nuclear factor-1β gene due to germline mosaicism. J. Clin. Endocrinol. Metab. 89, 2905–2908 (2004).
Gloyn, A. L. et al. Activating mutations in the gene encoding the ATP-sensitive potassium-channel subunit Kir6.2 and permanent neonatal diabetes. N. Engl. J. Med. 350, 1838–1849 (2004).
Babenko, A. P. et al. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N. Engl. J. Med. 355, 456–466 (2006).
Støy, J. et al. Insulin gene mutations as a cause of permanent neonatal diabetes. Proc. Natl Acad. Sci. USA 104, 15040–15044 (2007).
The International Pancreatic Agenesis Consortium. GATA6 haploinsufficiency causes pancreatic agenesis in humans. Nat. Genet. 44, 20–22 (2012).
van den Ouweland, J. M. et al. Mutation in mitochondrial tRNA(Leu)(UUR) gene in a large pedigree with maternally transmitted type II diabetes mellitus and deafness. Nat. Genet. 1, 368–371 (1992).
Nagamine, K. et al. Positional cloning of the APECED gene. Nat. Genet. 17, 393–398 (1997).
Finnish-German APECED Consortium. An autoimmune disease, APECED, caused by mutations in a novel gene featuring two PHD-type zinc-finger domains. Nat. Genet. 17, 399–403 (1997).
Stoffers, D. A., Zinkin, N. T., Stanojevic, V., Clarke, W. L. & Habener, J. F. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat. Genet. 15, 106–110 (1997).
Inoue, H. et al. A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nat. Genet. 20, 143–148 (1998).
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 66, 2044–2053 (2017).
Delépine, M. et al. EIF2AK3, encoding translation initiation factor 2-alpha kinase 3, is mutated in patients with Wolcott–Rallison syndrome. Nat. Genet. 25, 406–409 (2000).
Bennett, C. L. et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat. Genet. 27, 20–21 (2001).
Sellick, G. S. et al. Mutations in PTF1A cause pancreatic and cerebellar agenesis. Nat. Genet. 36, 1301–1305 (2004).
Senée, V. et al. Mutations in GLIS3 are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism. Nat. Genet. 38, 682–687 (2006).
Yasuda, T. et al. PAX6 mutation as a genetic factor common to aniridia and glucose intolerance. Diabetes 51, 224–230 (2002).
Kofoed, E. M. et al. Growth hormone insensitivity associated with a STAT5b mutation. N. Engl. J. Med. 349, 1139–1147 (2003).
Amr, S. et al. A homozygous mutation in a novel zinc-finger protein, ERIS, is responsible for Wolfram syndrome 2. Am. J. Hum. Genet. 81, 673–683 (2007).
Smith, S. B. et al. Rfx6 directs islet formation and insulin production in mice and humans. Nature 463, 775–780 (2010).
Rubio-Cabezas, O. et al. Homozygous mutations in NEUROD1 are responsible for a novel syndrome of permanent neonatal diabetes and neurological abnormalities. Diabetes 59, 2326–2331 (2010).
Rubio-Cabezas, O. et al. Permanent neonatal diabetes and enteric anendocrinosis associated with biallelic mutations in NEUROG3. Diabetes 60, 1349–1353 (2011).
Poulton, C. J. et al. Microcephaly with simplified gyration, epilepsy, and infantile diabetes linked to inappropriate apoptosis of neural progenitors. Am. J. Hum. Genet. 89, 265–276 (2011).
Boonen, S. E. et al. Transient neonatal diabetes, ZFP57, and hypomethylation of multiple imprinted loci: a detailed follow-up. Diabetes Care 36, 505–512 (2013).
Bonnefond, A. et al. Transcription factor gene MNX1 is a novel cause of permanent neonatal diabetes in a consanguineous family. Diabetes Metab. 39, 276–280 (2013).
Synofzik, M. et al. Absence of BiP co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration. Am. J. Hum. Genet. 95, 689–697 (2014).
Flanagan, S. E. et al. Activating germline mutations in STAT3 cause early-onset multi-organ autoimmune disease. Nat. Genet. 46, 812–814 (2014).
Flanagan, S. E. 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. 19, 146–154 (2014).
Kerns, S. L. et al. A novel variant in CDKN1C is associated with intrauterine growth restriction, short stature, and early-adulthood-onset diabetes. J. Clin. Endocrinol. Metab. 99, E2117–E2122 (2014).
Abdulkarim, B. et al. A missense mutation in PPP1R15B causes a syndrome including diabetes, short stature and microcephaly. Diabetes 64, 3951–3962 (2015).
Johnson, M. B. et al. Recessively inherited LRBA mutations cause autoimmunity presenting as neonatal diabetes. Diabetes 66, 2316–2322 (2017).
Şıklar, Z. et al. Monogenic diabetes not caused by mutations in mody genes: a very heterogenous group of diabetes. Exp. Clin. Endocrinol. Diabetes 126, 612–618 (2018).
Stekelenburg, C. et al. Exome sequencing identifies a de novo FOXA2 variant in a patient with syndromic diabetes. Pediatr. Diabetes 20, 366–369 (2019).
De Franco, E. et al. A specific CNOT1 mutation results in a novel syndrome of pancreatic agenesis and holoprosencephaly through impaired pancreatic and neurological development. Am. J. Hum. Genet. 104, 985–989 (2019).
De Franco, E. et al. YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress. J. Clin. Invest. 130, 6338–6353 (2020).
De Franco, E. et al. De novo mutations in EIF2B1 affecting eIF2 signaling cause neonatal/early onset diabetes and transient hepatic dysfunction. Diabetes 69, 477–483 (2020).
Lekszas, C. et al. Biallelic TANGO1 mutations cause a novel syndromal disease due to hampered cellular collagen secretion. eLife 9, e51319 (2020).
Chaimowitz, N. S., Ebenezer, S. J., Hanson, I. C., Anderson, M. & Forbes, L. R. STAT1 gain of function, type 1 diabetes, and reversal with JAK inhibition. N. Engl. J. Med. 383, 1494–1496 (2020).
Montaser, H. et al. Loss of MANF causes childhood-onset syndromic diabetes due to increased endoplasmic reticulum stress. Diabetes 70, 1006–1018 (2021).
Blodgett, D. M. et al. Novel observations from next-generation RNA sequencing of highly purified human adult and fetal islet cell subsets. Diabetes 64, 3172–3181 (2015).
Alonso, L. et al. TIGER: The gene expression regulatory variation landscape of human pancreatic islets. Cell Rep. 37, 109807 (2021).
Bansal, V. et al. Spectrum of mutations in monogenic diabetes genes identified from high-throughput DNA sequencing of 6888 individuals. BMC Med. 15, 213 (2017).
Goodrich, J. K. et al. Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes. Nat. Commun. 12, 3505 (2021).
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).
The authors declare no competing interests.
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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