The application of precision medicine in monogenic diabetes

References

• Johnson MB, Patel KA, and De Franco E, et al. Type 1 diabetes can present before the age of 6 months and is characterised by autoimmunity and rapid loss of beta-cells. Diabetologia. 2020;63(12):2605–2615.
   PubMed Web of Science ®Google Scholar
• Temple IK, James RS, Crolla JA, et al. An imprinted gene(s) for diabetes ? Nat Genet. 1995;9:110–112.
   PubMed Web of Science ®Google Scholar
• Babenko AP, Polak M, Cave H, et al. Activating mutations in the ABCC8 gene in neonatal diabetes mellitus. N Engl J Med. 2006;355:456–466.
   PubMed Web of Science ®Google Scholar
• Massa O, Iafusco D, D’Amato E, et al. KCNJ11 activating mutations in Italian patients with permanent neonatal diabetes. Hum Mutat. 2005;25:22–27.
   PubMed Web of Science ®Google Scholar
• Habeb AM, Flanagan SE, Deeb A, et al. Permanent neonatal diabetes: different aetiology in Arabs compared to Europeans. Arch Dis Child. 2012;97:721–723.
   PubMed Web of Science ®Google Scholar
• Bonfanti R, Iafusco D, Rabbone I, et al. Differences between transient neonatal diabetes mellitus subtypes can guide diagnosis and therapy. Eur J Endocrinol. 2021;184:575–585.
   PubMedGoogle Scholar
• Gloyn AL, Pearson ER, Antcliff JF, et al. Activating mutations in the ATP-sensitive potassium channel subunit Kir6.2 gene are associated with permanent neonatal diabetes. N Engl J Med. 2004;350:1838–1849.
   PubMed Web of Science ®Google Scholar
• Docherty LE, Kabwama S, and Lehmann A, et al. Clinical presentation of 6q24 transient neonatal diabetes mellitus (6q24 TNDM) and genotype-phenotype correlation in an international cohort of patients. Diabetologia. 2013*;56:758–762.
   PubMed Web of Science ®Google Scholar
• Pipatpolkai T, Usher S, and Stansfeld PJ, et al. New insights into KATP channel gene mutations and neonatal diabetes mellitus. Nat Rev Endocrinol. 2020**;16:378–393.
   PubMed Web of Science ®Google Scholar
• Abali ZV, De Franco E, Ozturan EK, et al. Clinical characteristics, molecular features, and long-term follow up of 15 patients with neonatal diabetes: a single-centre experience. Horm Res Paediatr. 2020;93:423–432.
   PubMed Web of Science ®Google Scholar
• Russo L, Iafusco D, Brescianini S, et al. Permanent diabetes during the first year of life: multiple gene screening in 54 patients. Diabetologia. 2011;54(7):1693–1701.
   PubMed Web of Science ®Google Scholar
• Ellard S, Flanagan SE, Girard SA, et al. Permanent diabetes caused by dominant, recessive or compound heterozygous SUR1 mutations with opposite functional effects. Am J Hum Genet. 2007;81(2):375–382.
   PubMed Web of Science ®Google Scholar
• Garin I, Edghill EL, Akerman I, et al. Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis. Proc Natl Acad of Sci USA. 2010;107(7):3105–3110.
   PubMed Web of Science ®Google Scholar
• Støy J, Edghill EL, Flanagan SE, et al. Insulin gene mutations as a cause of permanent neonatal diabetes. Proc Natl Acad Sci USA. 2007;104:15040–15044.
   PubMed Web of Science ®Google Scholar
• Colombo C, Porzio O, Liu M, et al. Seven mutations in the human insulin gene linked to permanent neonatal/infancy-onset diabetes mellitus. J Clin Invest. 2008;118:2148–2156.
   PubMed Web of Science ®Google Scholar
• Njolstad PR, Sovik O, Cuesta-Munoz A, et al. Neonatal diabetes mellitus due to complete glucokinase deficiency. N Engl J Med. 2001;344:1588–1592.
   PubMed Web of Science ®Google Scholar
• Prisco F, Iafusco D, Franzese A, et al. MODY 2 presenting as neonatal hyperglycaemia: a need to reshape the definition of “neonatal diabetes? Diabetologia. 2000;43:1331–1332.
   PubMed Web of Science ®Google Scholar
• Nicolino M, Claiborn KC, Senée V, et al. A novel hypomorphic PDX1 mutation responsible for permanent neonatal diabetes with subclinical exocrine deficiency. Diabetes. 2010;59:733–740.
   PubMed Web of Science ®Google Scholar
• De Franco E, Shaw-Smith C, SE F, et al. Biallelic PDX1 (insulin promoter factor 1) mutations causing neonatal diabetes without exocrine pancreatic insufficiency. Diabet Med. 2013;30:e197–e200.
   PubMed Web of Science ®Google Scholar
• Sansbury SH, Flanagan SE, Houghton JAL, et al. SLC2A2 mutations can cause neonatal diabetes, suggesting GLUT2 may have a role in human insulin secretion. Diabetologia. 2012;55:2381–2385.
   PubMed Web of Science ®Google Scholar
• Stoffers DA, Zinkin NT, Stanojevic V, et al. Pancreatic agenesis attributable to a single nucleotide deletion in the human IPF1 gene coding sequence. Nat Genet. 1997;15:106–110.
   PubMed Web of Science ®Google Scholar
• Weedon MN, Cebola I, Patch A-M, et al. Recessive mutations in a distal PTF1A enhancer cause isolated pancreatic agenesis. Nat Genet. 2014;46:61–64.
   PubMed Web of Science ®Google Scholar
• Demirbelek H, Cayir A, Flanagan SE, et al. Clinical characteristics and long-term follow-up of patients with diabetes due to PTF1A enhancer mutations. J Clin Endocrinol Metab. 2020;105:1–9.
   Web of Science ®Google Scholar
• Lango Allen H, Flanagan SE, Shaw-Smith C, et al. GATA6 haploinsufficiency causes pancreatic agenesis in humans. Nat Genet. 2012;44:20–22.
   Web of Science ®Google Scholar
• Shaw-Smith C, De Franco E, Lango Allen H, et al. GATA4 mutations are a cause of neonatal and childhood-onset diabetes. Diabetes. 2014;63:2888–2894.
   PubMed Web of Science ®Google Scholar
• Xuan S, Borok MJ, Decker KJ, et al. Pancreas-specific deletion of mouse Gata4 and Gata6 causes pancreatic agenesis. J Clin Invest. 2012;122:3516–3528.
   PubMed Web of Science ®Google Scholar
• Shi Z-D, Lee K, Yang D, et al. Genome editing in hPSCs reveals GATA6 haploinsufficiency and a genetic interaction with GATA4 in human pancreatic development. Cell Stem Cell. 2017;20:675–688.
   PubMed Web of Science ®Google Scholar
• De Franco E, Shaw-Smith C, Flanagan SE, et al. GATA6 mutations cause a broad phenotypic spectrum of diabetes from pancreatic agenesis to adult-onset diabetes without exocrine pancreatic insufficiency. Diabetes. 2013;62:993–997.
   PubMed Web of Science ®Google Scholar
• DeFranco E, Flanagan SE, Houghton JAL, et al. The effect of early, comprehensive genomic testing on clinical care in neonatal diabetes: an international cohort study. Lancet. 2015;386:957–963. **(**This seminal paper shows the different results of genomic testing conducted in patients from countries with low and high consanguineity rate).
   PubMed Web of Science ®Google Scholar
• Senée V, Chelala C, Duchatelet S, et al. Mutations in GLIS3 are responsible for a rare syndrome with neonatal diabetes mellitus and congenital hypothyroidism. Nat Genet. 2006;32:682–687.
   Google Scholar
• Sellick GS, Barker KT, Stolte-Dijkstra I, et al. Mutations in PTF1A cause pancreatic and cerebellar agenesis. Nat Genet. 2004;36:1301–1305.
   PubMed Web of Science ®Google Scholar
• Rubio-Cabezas O, Milton JAL, Kantor I, et al. Homozygous mutations in NEUROD1 are responsible for a novel syndrome of permanent neonatal diabetes and neurological abnormalities. Diabetes. 2010;59:2326–2331.
   PubMed Web of Science ®Google Scholar
• Demirbilek H, Hatipoglu N, Gul U, et al. Permanent neonatal diabetes mellitus and neurological abnormalities due to a novel homozygous missense mutation in NEUROD1. Pediatr Diabetes. 2018;19. 898–904.
   PubMed Web of Science ®Google Scholar
• Naya FJ, Huang H-P, Qiu Y, et al. Diabetes, defective pancreatic morphogenesis, and abnormal enteroendocrine differentiation in BETA2/NeuroD-deficient mice. Genes Dev. 1997;11:2323–2334.
   PubMed Web of Science ®Google Scholar
• Smith SB, Qu HQ, Taleb N, et al. Rfx6 direct islet formation and insulin production in mice and humans. Nature. 2010;463:775–780.
   PubMed Web of Science ®Google Scholar
• Mitchell J, Punthakee Z, Lo B, et al. Neonatal diabetes, with hypoplastic pancreas, intestinal atresia and gall bladder hypoplasia: search for the aetiology of a new autosomal recessive syndrome. Diabetologia. 2004;47:2160–2167.
   PubMed Web of Science ®Google Scholar
• Piccand J, Strasser P, Hodson DJ, et al. Rfx6 maintains the functional identity of adult pancreatic b cells. Cell Rep. 2014;9:2219–2232.
   PubMed Web of Science ®Google Scholar
• Chandra V, Albagli-Curiel O, Hastoy B, et al. RFX6 regulates insulin secretion by modulating Ca2+ homeostasis in human b cells. Cell Rep. 2014;9:2206–2218.
   PubMed Web of Science ®Google Scholar
• Zhu Z, Li QV, Lee K, et al. Genome editing of lineage determinants in human pluripotent stem cells reveals mechanisms of pancreatic development and diabetes. Cell Stem Cell. 2016;18:755–786. **(**This important paper illustrates the formidable power of pluripotent stem cell technology to study endocrine pancreas biology).
   PubMed Web of Science ®Google Scholar
• Trott J, Alpagu Y, Tan EK, et al. Mitchell-Riley syndrome iPSCs exhibit reduced pancreatic endoderm differentiation due to a mutation in RFX6. Development. 2020;147:dev194878.
   PubMed Web of Science ®Google Scholar
• Haumaitre C, Fabre M, Cormier S, et al. Severe pancreas hypoplasia and multicystic renal dysplasia in two human fetuses carrying novel HNF1beta/MODY5 mutations. Hum Mol Genet. 2006;15:2363–2375.
   PubMed Web of Science ®Google Scholar
• Yorifuji T, Kurokawa K, Mamada M, et al. Neonatal diabetes mellitus and neonatal polycystic, dysplastic kidneys: phenotypically discordant recurrence of a mutation in the hepatocyte nuclear factor-1b gene due to a germline mosaicism. J Clin Endocrinol Metab. 2004;89:2905–2908.
   PubMed Web of Science ®Google Scholar
• Al‐Khawaga S, Mohammed I, Saraswathi S, et al. The clinical and genetic characteristics of permanent neonatal diabetes (PNDM) in the state of Quatar. Mol Genet Genomic Med. 2019;7:e00753.
   PubMed Web of Science ®Google Scholar
• De Franco E, Watson RA, Weninger WJ, 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. 2019;104:985–989.
   PubMed Web of Science ®Google Scholar
• Kruszka P, Berger SI, Weiss K, et al. A CCR4-NOT transcription complex, subunit 1, CNOT1, variant associated with holoprosencephaly. Am J Hum Genet. 2019;104:990–993.
   PubMed Web of Science ®Google Scholar
• Wang J, Cortina G, Wu SV, et al. Mutant neurogenin-3 in congenital malabsorptive diarrhea. N Engl J Med. 2006;355:270–280.
   PubMed Web of Science ®Google Scholar
• Jensen JN, Rosenberg LC, Hecksher-Sørensen J, et al. Mutant neurogenin-3 in congenital malabsorptive diarrhea. N Engl J Med. 2007;356:1781–1782.
   PubMed Web of Science ®Google Scholar
• Rubio-Cabezas O, Jensen JN, Hodgson MI, et al. Permanent neonatal diabetes and enteric anendocrinosis associated with biallelic mutations in NEUROG3. Diabetes. 2011;60:1349–1353.
   PubMed Web of Science ®Google Scholar
• Azab B, Dardas Z, Rabab’h O, et al. Enteric anendocrinosis attributable to a novel Neurogenin-3 variant. Eur J Med Genet. 2020;63:103981.
   PubMed Web of Science ®Google Scholar
• Zhang X, McGrath PS, Salomone J, et al. A comprehensive structure-function study of Neurogenin3 disease-causing alleles during human pancreas and intestinal organoid development. Dev Cell. 2019;50:367–80.e7.
   PubMed Web of Science ®Google Scholar
• Flanagan SE, De Franco E, Lango Allen H, et al. Analysis of transcription factors key for mouse pancreatic development establishes NKX2-2 and MNX1 mutations as cause of neonatal diabetes in man. Cell Metab. 2014;19:146–154. *(*An important paper investigating the role of transcription factors in pancres development and disease).
   PubMed Web of Science ®Google Scholar
• Auerbach A, Cohen A, Ofek Shlomai N, et al. NKX2-2 mutation causes congenital diabetes and infantile obesity with paradoxical glucose-induced ghrelin secretion. J Clin Endocrinol Metab. 2020;105:dgaa563.
   PubMed Web of Science ®Google Scholar
• Sussel L, Kalamaras J, and Hartigan-O’Connor DJ, et al. Mice lacking the homeodomain transcription factor Nkx2.2 have diabetes due to arrested differentiation of pancreatic beta-cells. Development. 1998;125:2213–2221.
   PubMed Web of Science ®Google Scholar
• Qi Y, Cai J, Wu Y, et al. Control of oligodendrocyte differentiation by the Nkx2.2 homeodomain transcription factor. Development. 2001;128:2723–2733.
   PubMed Web of Science ®Google Scholar
• Mastracci TL, Lin C-S, Sussel L. Generation of mice encoding a conditional allele in Nkx2.2. Transgenic Res. 2013;22:965–972.
   PubMed Web of Science ®Google Scholar
• Pan FC, Brissova M, Powers AC, et al. Inactivating the permanent neonatal diabetes gene Mnx1 switches insulin-producing β-cells to a d-like fate and reveals a facultative proliferative capacity in aged β-cells. Development. 2015;142:3637–3648.
   PubMed Web of Science ®Google Scholar
• Solomon BD, Pineda-Alvarez DE, Balog JZ, et al. Compound heterozygosity for mutations in PAX6 in a patient with complex brain anomaly, neonatal diabetes mellitus, and microphthalmia. Am J Med Genet PartA. 2009;149A. 2543–2546.
   Google Scholar
• Hart AW, Mella S, Mendrychowski J, et al. The developmental regulator Pax6 is essential for maintenance of islet cell function in the adult mouse pancreas. PLoS ONE. 2013;8:e54173.
   PubMed Web of Science ®Google Scholar
• Poulton CJ, Schot R, and Kheradmand Kia S, et al. Microcephaly with simplified gyration,epilepsy, and infantile diabetes linked to inappropriate apoptosis of neural progenitors. Am J Hum Gen. 2011;89:265–276.
   PubMed Web of Science ®Google Scholar
• Abdel-Salam GMH, Schaffer AE, Zaki MS, et al. A homozygous IER3IP1 mutation causes microcephaly with simplified gyral pattern, epilepsy, and permanent neonatal diabetes syndrome (MEDS. Am J Med Genet Part A. 2012;158A:2788–2796.
   PubMed Web of Science ®Google Scholar
• Valenzuela I, Boronat S, Martínez-Sáez E, et al. Microcephaly with simplified gyral pattern, epilepsy and permanent neonatal diabetes syndrome (MEDS). A new patient and review of the literature. Eur J Med Genet. 2017;60:517–520.
   PubMed Web of Science ®Google Scholar
• Flanagan SE, Patch AM, Mackay DJ, et al. Mutations in ATP-sensitive K+ channel genes cause transient neonatal diabetes and permanent diabetes in childhood or adulthood. Diabetes. 2007;56:1930–1937.
   PubMed Web of Science ®Google Scholar
• Liu M, Sun J, and Cui J, et al. INS-gene mutations: from genetics and beta-cell biology to clinical disease. Mol Aspect Med. 2015;42:3–18.
   PubMed Web of Science ®Google Scholar
• Sumnik Z, Kolouskova S, Wales JKH, et al. Sulphonylurea treatment does not improve psychomotor development in children with KCNJ11 mutations causing permanent neonatal diabetes mellitus accompanied by developmental delay and epilepsy (DEND syndrome). Diabetic Med. 2007;24:1172–1178.
   PubMed Web of Science ®Google Scholar
• Senée V, Vattem KM, Delépine M, et al. Clinical, genetic and functional study of EIF2AK3 mutations and suggestion of genetic heterogeneity. Diabetes. 2004;53:1876–1883.
   PubMed Web of Science ®Google Scholar
• Julier C, Nicolino M. Wolcott-Rallison Syndrome. Orphanet J Rare Dis. 2010;5:29.
   PubMed Web of Science ®Google Scholar
• Tzakis AG, Nunnelley MJ, Tekin A, et al. Liver, pancreas and kidney transplantation for the treatment of Wolcott-rallison syndrome. Am J Transplant. 2015;15:565–567.
   PubMed Web of Science ®Google Scholar
• Harding HP, Zeng H, Zhang Y, et al. Diabetes mellitus and exocrine pancreatic dysfunction in Perk -/- mice reveals a role for translational control in secretory cell survival. Mol Cell. 2001;7:1153–1163.
   PubMed Web of Science ®Google Scholar
• Zhang P, McGrath B, Li S, et al. The PERK eukaryotic initiation factor 2a kinase is required for the development of skeletal system, postnatal growth and the function and viability of the pancreas. Mol Cell Biol. 2002;22:3864–3874.
   PubMed Web of Science ®Google Scholar
• Cavener DR, Gupta S, and McGrath BC. PERK in beta-cell biology and insulin biogenesis. Trends Endocrinol Metab. 2010;21:714–721.
   PubMed Web of Science ®Google Scholar
• De Franco E, Caswell R, Johnson MB, et al. De novo mutations in EIF2B1 affecting eIF2 signaling cause neonatal/early onset diabetes and transient hepatic dysfunction. Diabetes. 2020;69:477–483.
   PubMed Web of Science ®Google Scholar
• Steinmüller R, Steinberger D, Müller U. MEHMO (mental retardation, epileptic seizures, hypogonadism and -genitalism, microcephaly, obesity), a novel syndrome: assignment of disease locus to Xp21.1-p22.13. Eur J Hum Genet. 1998;6:201–206.
   PubMed Web of Science ®Google Scholar
• Skopkova M, Hennig F, Shin B-S, et al. EIF2S3 mutations associated with severe X-linked intellectual disability syndrome MEHMO. Hum Mutat. 2017;38:409–425.
   PubMed Web of Science ®Google Scholar
• De Franco E, Lytrivi M, Ibrahim H, et al. YIPF5 mutations cause neonatal diabetes and microcephaly through endoplasmic reticulum stress. J Clin Invest. 2020;130:6338–6353.
   PubMed Web of Science ®Google Scholar
• Rubio-Cabezas O, Flanagan SE, and Damhuis A, et al. KATP channel mutations in infants with permanent diabetes diagnosed after 6 months of life. Pediatr Diabetes. 2012;13:322–325.
   PubMed Web of Science ®Google Scholar
• Stanik J, Skopkova M, Stanikova D, et al. Neonatal hypoglycemia, early-onset diabetes and hypopituitarism due to the mutation in EIF2S3 gene causing MEHMO syndrome. Physiol Res. 2018;67:331–337.
   PubMed Web of Science ®Google Scholar
• Iafusco D, Stazi MA, Cotichini R, et al. Permanent diabetes in the first year of life. Diabetologia. 2002;45:798–804.
   PubMed Web of Science ®Google Scholar
• Wildin RS, Ramsdell F, Peake J, et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet. 2001;27:18–20.
   PubMed Web of Science ®Google Scholar
• Bennett CL, Christie J, Ramsdell F, et al. The immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (IPEX) is caused by mutations of FOXP3. Nat Genet. 2001;27:20–22.
   PubMed Web of Science ®Google Scholar
• Johnson MB, Hattersley AT, Flanagan SE. Monogenic autoimmune diseases of the endocrine system. Lancet Diab Endocrinol. 2016;4:862–872.
   PubMed Web of Science ®Google Scholar
• Chaimowitz NS, Ebenezer SJ, Hanson IC, et al. STAT1 gain of function, type 1 diabetes, and reversal with JAK inhibition. N Engl J Med. 2020;383:1494–1496.
   PubMed Web of Science ®Google Scholar
• Bowman P, Sulen A, and Barbetti F, 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. 2018;6:637–646.
   PubMed Web of Science ®Google Scholar
• Bowman P, Mathews F, Barbetti F, et al. Long-term follow-up of glycemic and neurological outcomes in an international series of patients with sulfonylurea-treated ABCC8 permanent neonatal diabetes. Diabetes Care. 2021;44:35–42.
   PubMed Web of Science ®Google Scholar
• Rabbone I, Barbetti F, and Gentilella R, et al. Insulin therapy in neonatal diabetes mellitus: a review of the literature. Diabetes Res Clin Pract . 2017;129. 126–135.
   PubMed Web of Science ®Google Scholar
• Barbetti F,D, Annunzio G. Genetic causes and treatment of neonatal diabetes and early childhood diabetes. Best Pract Res Clin Endocrinol Metab. 2018;32:575–591.
   PubMed Web of Science ®Google Scholar
• Froguel P, Zouali H, Vionnet N, et al. Familial hyperglycemia due to mutations in glucokinase. N Engl J Med. 1993;328:697–702.
   PubMed Web of Science ®Google Scholar
• Velho G, Blanché H, Vaxillaire M, et al. Identification of 14 new glucokinase mutations an description of the clinical profile of 42 MODY-2 families. Diabetologia. 1997;40:217–224.
   PubMed Web of Science ®Google Scholar
• The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Follow-up report on the diagnosis of diabetes mellitus. Diabetes Care 26:3160–3167, 2003
   Google Scholar
• Lorini R, Alibrandi A, Vitali LK, et al. Risk of type 1 diabetes development in children with incidental hyperglycemia. Diabetes Care. 2001;24:1210–1216.
   PubMed Web of Science ®Google Scholar
• Lorini R, Klersy C D, Annunzio G, et al. Maturity-onset diabetes of the young in children with incidental hyperglycemia. A multicenter Italian study of 172 families. Diabetes Care. 2009;32:1864–1866.
   PubMed Web of Science ®Google Scholar
• Delvecchio M, Mozzillo E, Salzano G, et al. Monogenic diabetes accounts for 6.3% of cases referred to 15 Italian pediatric diabetes centers during 2007-2012. J Clin Endocrinol Metab. 2017;102:1826–1834.
   PubMed Web of Science ®Google Scholar
• Raimondo A, Chakera AJ, Thomsen SK, 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. 2014;23:6432–6440.
   PubMed Web of Science ®Google Scholar
• Grupe A, Hultgren B, Ryan A, et al. Transgenic knockouts reveal a critical requirement for pancreatic b cell glucokinase in maintaining glucose homeostasis. Cell. 1995;83:69–78.
   PubMed Web of Science ®Google Scholar
• Delvecchio M, Ludovico O, Menzaghi C, et al. Low prevalence of HNF1A mutations after molecular screening of multiple MODY genes in 58 Italian families recruited in the pediatric or adult diabetes clinic from a single Italian hospital. Diabetes Care. 2014;37:e258–60.
   PubMed Web of Science ®Google Scholar
• Stride A, Vaxillaire M, Tuomi T, et al. The genetic abnormality in the beta-cell determines the response to an oral glucose load. Diabetologia. 2002;45:427–435.
   PubMed Web of Science ®Google Scholar
• Kleinberger JW, Copeland KC, Gandica RG, et al. Monogenic diabetes in overweight and obese youth diagnosed with type 2 diabetes: the TODAY clinical trial. Genet Med. 2018;20:583–590.
   PubMed Web of Science ®Google Scholar
• Pontoglio M, Barra J, Hadchouel M, et al. Hepatocyte nuclear factor 1 inactivation results in hepatic dysfunction, phenylketonuria, and renal Fanconi syndrome. Cell. 1996;84:575–585.
   PubMed Web of Science ®Google Scholar
• Haliyur R, Tong X, Sanyoura M, et al. Human islets expressing HNF1A variant have defective β cell transcriptional regulatory networks. J Clin Invest. 2019;129:246–251.
   PubMed Web of Science ®Google Scholar
• Low BSJ, Lim CS, Shirley Ding SSL, et al. Decreased GLUT2 and glucose uptake contribute to insulin secretion defects in MODY3/HNF1A hiPSC-derived mutant β cells. Nat Commun. 2021;12:3133.
   Web of Science ®Google Scholar
• Cardenas-Diaz FL, Osorio-Quintero C, Diaz-Miranda MA, et al. Modeling monogenic diabetes using human ESCs reveals developmental and metabolic deficiencies caused by mutations in HNF1A. Cell Stem Cell. 2019;25:273–289.
   PubMed Web of Science ®Google Scholar
• Pontoglio M, Sreenan S, Roe M, et al. Defective insulin secretion in hepatocyte nuclear factor 1alpha-deficient mice. J Clin Invest. 1998;101(10):2215–2222.
   PubMed Web of Science ®Google Scholar
• Dukes ID, Sreenan S, Roe MW, et al. Defective pancreatic β-cell glycolytic signaling in hepatocyte nuclear factor-1a-deficient mice. J Biol Chem. 1998;273(38):24457–24464.
   PubMed Web of Science ®Google Scholar
• Shih DQ, Screenan S, Munoz KN, et al. Loss of HNF-1a function in mice leads to abnormal expression of genes involved in pancreatic islet development and metabolism. Diabetes. 2001;50(11):2472–2480.
   PubMed Web of Science ®Google Scholar
• Colclough K, Bellanne-Chantelot C, Saint-Martin C, et al. Mutations in the genes encoding the transcription factors hepatocyte nuclear factor 1 alpha and 4 alpha in maturity-onset diabetes of the young and hyperinsulinemic hypoglycemia. Hum Mutat. 2013;34(5):669–685.
   PubMed Web of Science ®Google Scholar
• Herman WH, Fajans SS, Ortiz FJ, et al. Abnormal insulin secretion, not insulin resistance, is the genetic or primary defect of MODY in the RW pedigree. Diabetes. 1994;43(1):40–46.
   PubMed Web of Science ®Google Scholar
• Gupta RK, Vatamaniuk MZ, Lee CS, et al. The MODY1 gene HNF-4α regulates selected genes involved in insulin secretion. J Clin Invest. 2005;115(4):1006–1015.
   PubMed Web of Science ®Google Scholar
• Kuo T, Du W, Miyachi Y, et al. Antagonistic epistasis of Hnf4α and FoxO1 metabolic networks through enhancer interactions in β-cell function. Mol Metab. 2021;53:101256.
   Web of Science ®Google Scholar
• Ng NHJ, Jasmen JB, Lim CS, et al. HNF4A Haploinsufficiency in MODY1 abrogates liver and pancreas differentiation from patient-derived induced pluripotent stem cells. iScience. 2019;16:192–205.
   PubMed Web of Science ®Google Scholar
• Dubois-Laforgue D, Cornu E, Saint-Martin C, 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. 2017;40(11):1436–1443.
   PubMed Web of Science ®Google Scholar
• Heidet L, Decramer S, Pawtowski A, et al. Spectrum of HNF1B mutations in a large cohort of patients who harbor renal diseases. Clin J Am Soc Nephrol. 2010;5(6):1079–1090.
   PubMed Web of Science ®Google Scholar
• Duval H, Michel-Calemard L, Gonzales M, et al. Fetal anomalies associated with HNF1B mutations: report of 20 autopsy cases. Prenat Diagn 36:744–751, 2016
   Google Scholar
• Bellanné-Chantelot C, Clauin S, Chauveau D, et al. Large genomic rearrangements in the hepatocyte nuclear Factor-1β (TCF2) gene are the most frequent cause of maturity-onset diabetes of the young type 5. Diabetes. 2005;54(11):3126–3132.
   PubMed Web of Science ®Google Scholar
• Pearson ER, Badman MK, Lockwood CR, et al. Contrasting diabetes phenotypes associated with hepatocyte nuclear factor-1alpha and −1beta mutations. Diabetes Care. 2004;27(5):1102–1107.
   PubMed Web of Science ®Google Scholar
• Ng N, Mijares Zamuner M, and Siddique N, et al. Genotype-phenotype correlations and response to glucose lowering therapy in subjects with HNF1β associated diabetes. 2022;59(1): 83–93. .
   Google Scholar
• Dubois-Laforgue D, Bellanné-Chantelot C, Charles, et al. Intellectual disability in patients with MODY due to hepatocyte nuclear factor 1B (HNF1B) molecular defects. Diabet Metab. 2017;43(1):89–92.
   Google Scholar
• Teo AK, Lau HH, Valdez IA, et al. Early developmental perturbations in a human stem cell model of MODY5/HNF1B pancreatic hypoplasia. Stem Cell Reports. 2016;6(3):357–367.
   PubMed Web of Science ®Google Scholar
• Stoffers DA, Ferrer J, Clarke WL, et al. Early-onset type II diabetes mellitus (MODY4) linked to IPF1. Nat Genet. 1997;17(2):138–139.
   PubMed Web of Science ®Google Scholar
• Stoffers DA, Stanojevic V, Habener JF. Insulin promoter factor-1 gene mutation linked to early-onset type 2 diabetes mellitus directs expression of a dominant-negative isoprotein. J Clin Invest. 1998;102(1):232–241.
   PubMed Web of Science ®Google Scholar
• Fajans SS, Bell GI, Paz VP, et al. Obesity and hyperinsulinemia in a family with pancreatic agenesis and MODY caused by the IPF1 mutation Pro63fsX60. Transl Res. 2010;156(1):7–14.
   PubMed Web of Science ®Google Scholar
• Ahlgren U, Jonsson J, Jonsson L, et al. β-Cell-specific inactivation of the mouse Ipf1/Pdx1 gene results in loss of the β-cell phenotype and maturity onset diabetes. Genes Dev. 1998;12(12):1763–1768.
   PubMed Web of Science ®Google Scholar
• Deng M, Xiao X, Zhou L, et al. First case report of maturity-onset diabetes of the young type 4 pedigree in a Chinese family. Front Endocrinol 10:406, 2019
   Google Scholar
• Schwitzgebel VM, Mamin A, Brun T, et al. Agenesis of human pancreas due to decreased half-life of insulin promoter factor 1. J Clin Endocrinol Metab. 2003;88(9):4398–4406.
   PubMed Web of Science ®Google Scholar
• Todd JN, Kleinberger JW, and Zhang H, et al. Monogenic diabetes in youth with presumed type 2 diabetes: results from the progress in diabetes genetics in youth (ProDiGY) collaboration. Diabetes Care, published online ahead of print, doi: https://doi.org/10.2337/dc21-0491 2021
   Google Scholar
• MT M, US J, Antonellis A, et al. Mutations in NEUROD1 are associated with the development of type 2 diabetes mellitus. Nat Genet. 1999;23(3):323–328.
   PubMed Web of Science ®Google Scholar
• Horikawa Y, and Enya M. Genetic dissection and clinical features of MODY6 (NEUROD1-MODY). Curr Diab Rep. 2019;19(3):12.
   PubMed Web of Science ®Google Scholar
• Anderson KR, Torres CA, Solomon K, et al. Cooperative transcriptional regulation of the essential pancreatic islet gene NeuroD1 (beta2) by Nkx2.2 and neurogenin 3. J Biol Chem. 2009;284(45):31236–31248.
   PubMed Web of Science ®Google Scholar
• Romer AI, Singer RA, Sui L, et al. Murine perinatal β-cell proliferation and the differentiation of human stem cell–derived insulin-expressing cells require NEUROD1. Diabetes. 2019;68(12):2259–2271.
   PubMed Web of Science ®Google Scholar
• Horikawa Y, Enya M, and Mabe H, et al. NEUROD1-deficient diabetes (MODY6): identification of the first cases in Japanese and the clinical features. Pediatr Diabetes. 2018;19(2):236–242.
   PubMed Web of Science ®Google Scholar
• Raeder H, Johansson S, Holm PI, et al. Mutations in the CEL VNTR cause a syndrome of diabetes and pancreatic exocrine dysfunction. Nat Genet. 2005;38(1):54–62.
   PubMed Web of Science ®Google Scholar
• Pellegrini S, Pipitone GB, Cospito A, et al. Generation of β Cells from iPSC of a MODY8 patient with a novel mutation in the carboxyl ester lipase (CEL) Gene. J Clin Endocrinol Metab. 2021;106(5):e2322–33.
   PubMed Web of Science ®Google Scholar
• Xiao X, Jones G, Sevilla WA, et al. A carboxyl ester lipase (CEL) mutant causes chronic pancreatitis by forming intracellular aggregates that activate apoptosis. J Biol Chem. 2016;291(44):23224–23236.
   PubMed Web of Science ®Google Scholar
• Patel KA, Kettunen J, and Laakso M, et al. Heterozygous RFX6 protein truncating variants are associated with MODY with reduced penetrance. Nat Commun. 2017;8(1): 888.
   PubMedGoogle Scholar
• Solorzano-Vargas RS, Bjerknes M, Wang J, et al. Null mutations of NEUROG3 are associated with delayed-onset diabetes mellitus. JCI Insight. 2020;5(1):e127657.
   PubMed Web of Science ®Google Scholar
• Iacovazzo D, Flanagan SE, Walker E, et al. MAFA missense mutation causes familial insulinomatosis and diabetes mellitus. Proc Natl Acad Sci. 2018;115(5):1027–1032.
   PubMed Web of Science ®Google Scholar
• Synofzik M, Haack TB, Kopajtich R, et al. Absence of BiP co-chaperone DNAJC3 causes diabetes mellitus and multisystemic neurodegeneration. Am J Hum Genet. 2014;95(6):689–697.
   PubMed Web of Science ®Google Scholar
• Ladiges WC, Knoblaugh SE, Morton JF, et al. Pancreatic beta-cell failure and diabetes in mice with a deletion mutation of the endoplasmic reticulum molecular chaperone gene P58IPK. Diabetes. 2005;54(4):1074–1081.
   PubMed Web of Science ®Google Scholar
• Lytrivi M, Senée V, Salpea P, et al. DNAJC3 deficiency induces β-cell mitochondrial apoptosis and causes syndromic young-onset diabetes. Eur J Endocrinol. 2021;184(3):455–468.
   PubMedGoogle Scholar
• Igoillo-Esteve M, Genin A, Lambert N, et al. tRNA methyltransferase homolog gene TRMT10A mutation in young onset diabetes and primary microcephaly in humans. PLoS Genet. 2013;9(10):e1003888.
   PubMed Web of Science ®Google Scholar
• Bohlega SA, and Abusrair A. Woodhouse-Sakati syndrome. 2016 Aug 4 [updated 2021 Jul 8]. In: Adam MP, Ardinger HH, and Pagon RA, et al., editors. GeneReviews® [Internet].Seattle (WA):University of Washington;Seattle 1993–2022.
   Google Scholar
• Alazami AM, Al-Saif A, Al-Semari A, et al. Mutations in C2orf37, encoding a nucleolar protein, cause hypogonadism, alopecia, diabetes mellitus, mental retardation, and extrapyramidal syndrome. Am J Hum Genet. 2008;83(6):684–691.
   PubMed Web of Science ®Google Scholar
• Cliffe ST, Kramer JM, Hussain K, et al. SLC29A3 gene is mutated in pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome and interacts with the insulin signaling pathway. Hum Mol Genet. 2009;18(12):2257–2265.
   PubMed Web of Science ®Google Scholar
• Molho-Pessach V, Ramot Y, Camille F, et al. H syndrome: the first 79 patients. J Am Acad Dermatol. 2014;70(1):80–88.
   PubMed Web of Science ®Google Scholar
• Ortigoza-Escobar JD, Molero-Luis M, Arias A, et al. Treatment of genetic defects of thiamine transport and metabolism. Exp Rev Neurother. 2016;16(7):755–763.
   PubMed Web of Science ®Google Scholar
• Jungtrakoon P, Shirakawa J, Buranasupkajorn P, et al. Loss-of-function mutation in thiamine transporter 1 in a family with autosomal dominant diabetes. Diabetes. 2019;68(5):1084–1093.
   PubMed Web of Science ®Google Scholar
• Potter K, Wu J, and Lauzon J, et al. Beta-cell function and clinical course in three siblings with thiamine-responsive megaloblastic anemia (TRMA) treated with thiamine supplementation. J Pediatr Endocrinol Metab. 2017;30:241–246.
   PubMed Web of Science ®Google Scholar
• Prudente S, Jungtrakoon P, Marucci A, et al. Loss-of-function mutations in APPL1 in familial diabetes mellitus. Am J Hum Genet. 2015;97(1):177–185.
   PubMed Web of Science ®Google Scholar
• Han W. Dual functions of adaptor protein, phosphotyrosine interaction, PH domain and leucine zipper containing 1 (APPL1) in insulin signaling and insulin secretion. Proceedings of the National Academy of Sciences. 2012;109(23):8795–8796.
   PubMed Web of Science ®Google Scholar
• Inoue H, Tanizawa Y, Wasson J, et al. A gene encoding a transmembrane protein is mutated in patients with diabetes mellitus and optic atrophy (Wolfram syndrome). Nat Genet. 1998;20(2):143–148.
   PubMed Web of Science ®Google Scholar
• Tranebjærg L, Barrett T, and Rendtorff ND. WFS1 Wolfram Syndrome Spectrum Disorder 2009 Feb 24 [updated 2020 Apr 9]. In: MP A, HH A, and RA P, et al. editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2022
   Google Scholar
• Ishihara H, Takeda, S, Tamura, A, et al. Disruption of the WFS1 gene in mice causes progressive -cell loss and impaired stimulus-secretion coupling in insulin secretion. Hum Mol Genet. 2004;13(11):1159–1170.
   PubMed Web of Science ®Google Scholar
• Yamada T, Ishihara H, Tamura A, et al. WFS1-deficiency increases endoplasmic reticulum stress, impairs cell cycle progression and triggers the apoptotic pathway specifically in pancreatic beta-cells. Hum Mol Genet. 2006;15:1600–1609.
   PubMed Web of Science ®Google Scholar
• Fonseca SG, Ishigaki S, Oslowski CM, et al. Wolfram syndrome 1 gene negatively regulates ER stress signaling in rodent and human cells. J Clin Invest. 2010;120:744–755.
   PubMed Web of Science ®Google Scholar
• Hu K, Zatyka M, Astuti D, et al. WFS1 protein expression correlates with clinical progression of optic atrophy in patients with Wolfram syndrome. J Med Genet. jmedgenet-2020-107257. DOI:https://doi.org/10.1136/jmedgenet-2020-107257. Online ahead of print.
   Google Scholar
• Saint-Martin C, Bouvet D, Bastide M, et al. Gene panel sequencing of patients with monogenic diabetes brings to light genes typically associated with syndromic presentations. Diabetes. 2021Sep23;db210520. doi:https://doi.org/10.2337/db21-0520 Online ahead of print
   Google Scholar
• Li M, Wang S, Xu K, 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;69:121–126.
   PubMed Web of Science ®Google Scholar
• Eiberg H, Hansen L, Kjer B, et al. Autosomal dominant optic atrophy associated with hearing impairment and impaired glucose regulation caused by a missense mutation in the WFS1 gene. J Med Genet. 2006;43:435–440.
   PubMed Web of Science ®Google Scholar
• Bonnycastle LL, Chines PS, Hara T, et al. Autosomal dominant diabetes arising from a Wolfram syndrome 1 mutation. Diabetes. 2013;62:3943–3950.
   PubMed Web of Science ®Google Scholar
• De Franco E, Flanagan SE, Yagi T, 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;66:2044–2053.
   PubMed Web of Science ®Google Scholar
• El-Shanti H, Lidral AC, Jarrah N, et al. Homozygosity mapping identifies an additional locus for Wolfram syndrome on chromosome 4q. Am J Hum Genet. 2000;66:1229–1236.
   PubMed Web of Science ®Google Scholar
• Mozzillo E, Delvecchio M, Carella M, et al. A novel CISD2 intragenic deletion, optic neuropathy and platelet aggregation defect in Wolfram syndrome type 2. BMC Med.Genet. 2014;15. 88.
   PubMed Web of Science ®Google Scholar
• Rondinelli M, Novara F, Calcaterra V, et al. Wolfram syndrome 2: a novel CISD2 mutation identified in Italian siblings. Acta Diabetol. 2015;52:175–178.
   PubMed Web of Science ®Google Scholar
• Pourreza MR, Sobhani M, Rahimi A, et al. Homozygosity mapping and direct sequencing identify a novel pathogenic variant in the CISD2 gene in an Iranian Wolfram syndrome family. Acta Diabetol. 2020;57:81–87.
   PubMed Web of Science ®Google Scholar
• Rouzier C, Moore D, Delorme C, et al. A novel CISD2 mutation associated with a classical Wolfram syndrome phenotype alters Ca2+ homeostasis and ER-mitochondria interactions. Hum Mol Genet. 2017;26:1599–1611.
   PubMed Web of Science ®Google Scholar
• Chen YF, Kao CH, Chen YT, et al. Cisd2 deficiency drives premature aging and causes mitochondria-mediated defects in mice. Genes Dev. 2009;23:1183–1194.
   PubMed Web of Science ®Google Scholar
• Chomyn A, Martinuzzi A, Yoneda M, et al. MELAS mutation in mtDNA binding site for transcription termination factor causes defects in protein synthesis and in respiration but no change in levels of upstream and downstream mature transcripts. Proc Natl Acad Sci USA. 1992;89:4221–4225.
   PubMed Web of Science ®Google Scholar
• Kadowaki T, Kadowaki H, Mori Y, et al. A subtype of diabetes mellitus associated with a mutation of mitochondrial DNA. N Engl J Med. 1994;330:962–968. *(*A paper revealing the importance of an often overlooked genetic defect leading to diabetes).
   PubMed Web of Science ®Google Scholar
• Guillausseau PJ, Massin P, Dubois-laforgue D, et al. Maternally inherited diabetes and deafness: a multicenter study. Ann Intern Med. 2001;134:721–728.
   PubMed Web of Science ®Google Scholar
• Philippi A, Heller S, Costa IG, et al. Mutations and variants of ONECUT1 in diabetes. Nat Med. 2021;27:1928–1940.
   PubMed Web of Science ®Google Scholar
• Heller S, Li Z, Lin Q, et al. Transcriptional changes and the role of ONECUT1 in hPSC pancreatic differentiation. Commun Biol. 2021;4:1298.
   PubMed Web of Science ®Google Scholar
• Liang L, Li X, Moutton S, et al. De novo loss-of-function KCNMA1 variants are associated with a new multiple malformation syndrome and a broad spectrum of developmental and neurological phenotypes. Hum Mol Genet. 2019;28:L2937–51.
   PubMed Web of Science ®Google Scholar
• Mameli C, Cazzola R, Spaccini L, et al. Neonatal diabetes in patients affected by Liang-Wang syndrome carrying KCNMA1 Variant p.(Gly375Arg) suggest a potential role of Ca 2+ and voltage-activated K + channel activity in human insulin secretion. Curr Issues Mol Biol. 2021;43:1036–1042.
   PubMed Web of Science ®Google Scholar
• Graff SM, Johnson SR, Leo PJ, et al. A KCNK16 mutation causing TALK-1 gain of function is associated with maturity-onset diabetes of the young. JCI Insight. 2021;6:e138057.
   PubMed Web of Science ®Google Scholar