Analysis of Mutation Site Structure Prediction and Family Characteristics of Maturity-Onset Diabetes of the Young (MODY) with Ketosis: Caused by HNF4α Gene Mutation.

OBJECTIVEIdentifying maturity-onset diabetes of the young (MODY) in pediatric populations close to diabetes diagnosis is difficult. Misdiagnosis and unnecessary insulin treatment are common. We aimed to identify the discriminatory clinical features at diabetes diagnosis of patients with glucokinase (GCK), hepatocyte nuclear factor-1A (HNF1A), and HNF4A MODY in the pediatric population.RESEARCH DESIGN AND METHODSSwedish patients (n = 3,933) aged 1–18 years, diagnosed with diabetes May 2005 to December 2010, were recruited from the national consecutive prospective cohort Better Diabetes Diagnosis. Clinical data, islet autoantibodies (GAD insulinoma antigen-2, zinc transporter 8, and insulin autoantibodies), HLA type, and C-peptide were collected at diagnosis. MODY was identified by sequencing GCK, HNF1A, and HNF4A, through either routine clinical or research testing.RESULTSThe minimal prevalence of MODY was 1.2%. Discriminatory factors for MODY at diagnosis included four islet autoantibody negativity (100% vs. 11% not-known MODY; P = 2 × 10−44), HbA1c (7.0% vs. 10.7% [53 vs. 93 mmol/mol]; P = 1 × 10−20), plasma glucose (11.7 vs. 26.7 mmol/L; P = 3 × 10−19), parental diabetes (63% vs. 12%; P = 1 × 10−15), and diabetic ketoacidosis (0% vs. 15%; P = 0.001). Testing 303 autoantibody-negative patients identified 46 patients with MODY (detection rate 15%). Limiting testing to the 73 islet autoantibody-negative patients with HbA1c <7.5% (58 mmol/mol) at diagnosis identified 36 out of 46 (78%) patients with MODY (detection rate 49%). On follow-up, the 46 patients with MODY had excellent glycemic control, with an HbA1c of 6.4% (47 mmol/mol), with 42 out of 46 (91%) patients not on insulin treatment.CONCLUSIONSAt diagnosis of pediatric diabetes, absence of all islet autoantibodies and modest hyperglycemia (HbA1c <7.5% [58 mmol/mol]) should result in testing for GCK, HNF1A, and HNF4A MODY. Testing all 12% patients negative for four islet autoantibodies is an effective strategy for not missing MODY but will result in a lower detection rate. Identifying MODY results in excellent long-term glycemic control without insulin.

Different diabetes

Clinical features, complications and treatment of rarer forms of maturity-onset diabetes of the young (MODY) - A review.

Diabetic ketoacidosis (DKA) is a medically fatal condition in poorly controlled hyperglycemia or newly diagnosed diabetes mellitus. Severe hypertriglyceridemia (HTG) is an uncommon complication of DKA and can be associated with acute pancreatitis (AP). We present the clinical manifestations, laboratory findings, and management of AP associated with HTG in a 14-year-old girl with DKA. The patient, with a 7-year history of type 2 diabetes presented with epigastric pain, 1 month after stopping insulin injection. DKA, severe HTG, and AP were diagnosed based on the laboratory and imaging tests. She recovered from DKA after conventional treatment for DKA, and her triglyceride (TG) level was reduced from 10,867 mg/dL to the normal range after 7 days of admission without antilipid medication. Given that her C-peptide level was not too low and considering her negative diabetes-related antibodies and high TG level, targeted gene panel sequencing was performed on the genes associated with diabetes and HTG. We identified a heterozygous mutation, c.4607C>T (p. Ala1537Val), in ABCC8 related to maturityonset diabetes of the young (MODY) 12. To our knowledge, this is the first reported case of HTG-induced AP with DKA in a patient with MODY. In addition, we reviewed the literature for pediatric cases of HTG with DKA. In patients with DKA, timely awareness of severe HTG related to insulin deficiency is crucial for improving the consequences of AP. We recommend considering AP in all DKA patients presenting with severe HTG to ensure early and proper management.

This study aimed to explore the distribution, trends, and clinical characteristics of various types of childhood diabetes, including type 1 diabetes (T1DM), type 2 diabetes (T2DM), and maturity-onset diabetes of the young (MODY) in a tertiary health center. We conducted a comprehensive review of medical records of individuals aged 0-18 years who were diagnosed with diabetes between January 1996 and December 2023. Clinical and laboratory characteristics at the time of diagnosis, along with the specific diabetes type, were meticulously documented. A total of 1219 patients were included in the study, of whom 48.4% were female, with a mean age at diagnosis of 9.1 ± 4.3 years. T1DM was diagnosed in 85.8% of patients, T2DM in 6.3%, clinical MODY in 5.2%, and rare forms of diabetes in 2.6%. An increasing trend in T2DM and MODY cases has been observed since 2007. Diabetic ketoacidosis (DKA) was most prevalent in T1DM (47.1%), followed by T2DM (5.2%) and MODY (1.6%). Mean C-peptide levels at diagnosis were 0.57 ± 0.5 ng/mL in T1DM, 3.2 ± 1.3 ng/mL in T2DM, and 1.4 ± 0.9 ng/mL in MODY. Antibody positivity was observed in 78.8% of T1DM, 6.5% of T2DM, and 15.9% of MODY cases. Among the MODY group, genetic analysis was performed in 48 (75%) patients, with GCK gene mutations identified as the most common genetic abnormality in 27 (56.2%) of these patients. This study demonstrates that T1DM is still the most commonly diagnosed type of diabetes in childhood, while T2DM and MODY are less frequent. However, a temporal increase in the incidence of MODY and T2DM subtypes was observed. The incidence of DKA at diagnosis was significantly higher in T1DM patients compared with those diagnosed with MODY or T2DM.

The yield of commercial gene panels for MODY has been reported as low as 27% suggesting the role of un-identified gene variants in MODY. We aimed to study novel genetic factors of MODY. We identified 10 probands who had clinical characteristics suggestive of MODY (i.e., positive family history of diabetes, negative islet autoantibodies, and diagnosis of diabetes at &amp;lt;25 y/o) but negative genetic test results on a commercial MODY gene panel. We performed whole-exome sequencing (WES) in probands and their parents. In each trio, we prioritized rare protein-altering variants (stop-gain, frameshift indels, splicing and missense variants) in 70 neonatal diabetes and MODY candidate genes. Mean age at diabetes diagnosis was 10 (± 3.8) years. Six were females; 4 were non-Hispanic white, 5 Hispanic, and 1 Asian. Previously assigned diabetes types were type 1 diabetes (T1D) (n=7), unknown (n=2) and ketosis-prone diabetes (n=1). We found a likely pathogenic, de novo variant in INS gene (c.94G&amp;gt;A, p.Gly32Ser), confirmed by Sanger sequencing, in a proband who was previously diagnosed with T1D at 3 y/o. This very rare variant, absent in the general population (gnomAD database), has been reported previously in multiple individuals with neonatal diabetes. We also identified a frameshift deletion (c.2650delC, p.Gln884AsnfsTer57) in RFX6 gene in a child with a previous diagnosis of T1D at 12 y/o. The variant was inherited from the mother, who was diagnosed with diabetes of unknown etiology at 25 y/o. Heterozygous protein-truncating variants in RFX6 gene have been recently reported in individuals with MODY. In conclusion, we identified two new MODY cases, with a novel variant not previously associated with MODY in one of them, using WES in children who were initially diagnosed with T1D. Our study demonstrates clinical utility of exome sequencing in atypical cases of diabetes suspected of MODY. Disclosure M. Tosur: None. A. Sabo: None. M.M. Khayat: None. S.N. Jhangiani: None. A.K. Refaey: None. D. Muzny: None. R.A. Gibbs: None. A. Balasubramanyam: None. M.J. Redondo: None. Funding Mike Hogg Fund

1. Justin M. Gregory, MD* 2. Daniel J. Moore, MD, PhD† 3. Jill H. Simmons, MD‡ 1. *Pediatric Endocrinology Clinical Fellow, Ian Burr Division of Pediatric Endocrinology and Diabetes, Vanderbilt University School of Medicine, Nashville, TN. 2. †Assistant Professor of Pediatrics, Assistant Professor of Pathology, Microbiology, and Immunology, Ian Burr Division of Pediatric Endocrinology and Diabetes, Vanderbilt University School of Medicine, Nashville, TN. 3. ‡Assistant Professor of Pediatrics, Ian Burr Division of Pediatric Endocrinology and Diabetes, Vanderbilt University School of Medicine, Nashville, TN. * ADA: : American Diabetes Association DKA: : diabetic ketoacidosis HbA1c: : glycosylated hemoglobin I:C ratio: : insulin-to-carbohydrate ratio IV: : intravenous TDD: : total daily dose T1DM: : type 1 diabetes mellitus T2DM: : type 2 diabetes mellitus 1. All children with type 1 diabetes mellitus (T1DM) should have their blood sugar managed with basal-bolus insulin treatment by either multiple daily injections or an insulin pump. 2. All children with T1DM should have access to a pediatric endocrinologist with a diabetes management team with resources to support patients and families. 3. All children with T1DM should be monitored for symptoms and/or screened for commonly associated conditions such as thyroid and celiac disease. After completing this article, readers should be able to: 1. Recognize the presenting signs and symptoms of type 1 diabetes mellitus (T1DM). 2. Know the key principles of effective diabetes self-management and the diabetes care team’s role in facilitating effective self-management. 3. Know the acute and chronic complications of (T1DM). 4. Identify how different categories of insulin analogues are used in daily insulin regimens. True, it is a fight, but there is pleasure in the struggle. Victory comes to the courageous; and without courage and common sense, success awaits no one. I look upon the diabetic as charioteer and his chariot as drawn by three steeds named Diet, Insulin, and Exercise. It takes skill to drive one horse, intelligence to manage a team of two, but a man must be a very good teamster who can get all three to pull together.EP Joslin, 1933 Type 1 diabetes mellitus (T1DM) is a disorder of glucose homeostasis characterized by autoimmune destruction of the insulin-producing pancreatic β-cell that progressively leads to insulin deficiency and resultant hyperglycemia. If left untreated, insulin deficiency leads to progressive metabolic derangement, with worsening hyperglycemia, ketoacidosis, starvation, and death. In …

Type 1 Diabetes Mellitus

The incidence of type 2 diabetes (T2D) is on the rise in youth in the US1Dabelea D. Mayer-Davis E.J. Saydah S. Imperatore G. Linder B. Divers J. et al.Prevalence of type 1 and type 2 diabetes among children and adolescents from 2001 to 2009.JAMA. 2014; 311: 1778-1786Crossref PubMed Scopus (933) Google Scholar,2Mayer-Davis E.J. Dabelea D. Lawrence J.M. Incidence trends of type 1 and type 2 diabetes among youths, 2002-2012.N Engl J Med. 2017; 377: 301Crossref PubMed Scopus (7) Google Scholar and worldwide.3Pinhas-Hamiel O. Zeitler P. The global spread of type 2 diabetes mellitus in children and adolescents.J Pediatr. 2005; 146: 693-700Abstract Full Text Full Text PDF PubMed Scopus (484) Google Scholar T2D is characterized by hyperglycemia from a combination of insulin resistance and relative deficiency of insulin secretion. The contribution of insulin resistance to diabetes pathogenesis explains the clinical association of diabetes with obesity and, subsequently, the coincidence of increasing T2D prevalence with increasing prevalence and severity of obesity in children.4Skinner A.C. Ravanbakht S.N. Skelton J.A. Perrin E.M. Armstrong S.C. Prevalence of obesity and severe obesity in US children, 1999-2016.Pediatrics. 2018; 141: e20173459Crossref PubMed Scopus (783) Google Scholar Differences have been described in the natural history of youth-onset T2D and adult-onset T2D. Compared with adults, T2D in youth appears to progress more rapidly, with higher rates of metformin treatment failure and more rapid rates of beta cell decline.5Zeitler P. Hirst K. Pyle L. Linder B. Copeland K. et al.TODAY Study GroupA clinical trial to maintain glycemic control in youth with type 2 diabetes.N Engl J Med. 2012; 366: 2247-2256Crossref PubMed Scopus (597) Google Scholar, 6Bacha F. Pyle L. Nadeau K. Cuttler L. Goland R. Haymond M. et al.Determinants of glycemic control in youth with type 2 diabetes at randomization in the TODAY study.Pediatr Diabetes. 2012; 13: 376-383Crossref PubMed Scopus (33) Google Scholar, 7Narasimhan S. Weinstock R.S. Youth-onset type 2 diabetes mellitus: lessons learned from the TODAY study.Mayo Clin Proc. 2014; 89: 806-816Abstract Full Text Full Text PDF PubMed Scopus (63) Google ScholarThe presence of diabetes encumbers those affected with a long-term burden of chronic disease and an increased risk of cardiovascular and microvascular complications. This risk increases with the duration of the disease, putting children with T2D at extremely high risk for complications. Follow-up data from both the SEARCH for Diabetes in Youth study and the Treatment Options for Diabetes in Youth (TODAY) trial have found a substantial presence of diabetes complications as early as adolescence and young adulthood.8TODAY Study GroupRapid rise in hypertension and nephropathy in youth with type 2 diabetes: the TODAY clinical trial.Diabetes Care. 2013; 36: 1735-1741Crossref PubMed Scopus (188) Google Scholar, 9TODAY Study GroupLipid and inflammatory cardiovascular risk worsens over 3 years in youth with type 2 diabetes: the TODAY clinical trial.Diabetes Care. 2013; 36: 1758-1764Crossref PubMed Scopus (122) Google Scholar, 10Maahs D.M. Snively B.M. Bell R.A. Dolan L. Hirsch I. Imperatore G. et al.Higher prevalence of elevated albumin excretion in youth with type 2 than type 1 diabetes: the SEARCH for Diabetes in Youth study.Diabetes Care. 2007; 30: 2593-2598Crossref PubMed Scopus (126) Google Scholar, 11Mayer-Davis E.J. Davis C. Saadine J. D'Agostino Jr., R.B. Dabelea D. Dolan L. et al.Diabetic retinopathy in the SEARCH for Diabetes in Youth cohort: a pilot study.Diabet Med. 2012; 29: 1148-1152Crossref PubMed Scopus (55) Google Scholar Moreover, the prevalence of complications and overall mortality are higher in youth with T2D compared with adults with T2D or even youth with type 1 diabetes.12Constantino M.I. Molyneaux L. Limacher-Gisler F. Al-Saeed A. Luo C. Wu T. et al.Long-term complications and mortality in young-onset diabetes: type 2 diabetes is more hazardous and lethal than type 1 diabetes.Diabetes Care. 2013; 36: 3863-3869Crossref PubMed Scopus (268) Google Scholar,13Dabelea D. Stafford J.M. Mayer-Davis E.J. D'Agostino Jr., R. Dolan L. Imperatore G. et al.Association of type 1 diabetes vs type 2 diabetes diagnosed during childhood and adolescence with complications during teenage years and young adulthood.JAMA. 2017; 317: 825-835Crossref PubMed Scopus (2) Google Scholar This burden of disease underscores the need to improve our understanding of diabetes risk, prevention, and optimal treatment in youth.T2D is a complex, multifactorial disease influenced by both environmental factors and genetic variation as well as their interactions.14Barroso I. McCarthy M.I. The genetic basis of metabolic disease.Cell. 2019; 177: 146-161Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar,15Kolb H. Martin S. Environmental/lifestyle factors in the pathogenesis and prevention of type 2 diabetes.BMC Med. 2017; 15: 131Crossref PubMed Scopus (256) Google Scholar The heritability of T2D is demonstrated by both the high concordance rates in identical twins16Barnett A.H. Eff C. Leslie R.D. Pyke D.A. Diabetes in identical twins. A study of 200 pairs.Diabetologia. 1981; 20: 87-93Crossref PubMed Scopus (835) Google Scholar,17Willemsen G. Ward K.J. Bell C.G. Christensen K. Bowden J. Dalgård C. et al.The concordance and heritability of type 2 diabetes in 34,166 twin pairs from international twin registers: the Discordant Twin (DISCOTWIN) Consortium.Twin Res Hum Genet. 2015; 18: 762-771Crossref PubMed Scopus (82) Google Scholar and the typical presence of a family history of T2D in those with the disease.18Copeland K.C. Zeitler P. Geffner M. Guandalini C. Higgins J. Hirst K. et al.Characteristics of adolescents and youth with recent-onset type 2 diabetes: the TODAY cohort at baseline.J Clin Endocrinol Metab. 2011; 96: 159-167Crossref PubMed Scopus (283) Google Scholar,19Klein B.E. Klein R. Moss S.E. Cruickshanks K.J. Parental history of diabetes in a population-based study.Diabetes Care. 1996; 19: 827-830Crossref PubMed Scopus (100) Google Scholar Investigations of the genetics of diabetes risk have examined both overall T2D risk as well as individual glycemic traits that may predispose to diabetes, such as fasting glucose levels, insulin secretion, insulin resistance, and β-cell function. Understanding the genetic underpinnings of diabetes risk offers an opportunity to improve both our knowledge of the mechanisms contributing to diabetes pathogenesis and our understanding of how best to individualize diabetes treatment and prevent complications. Here we review the current state of T2D genetics, specifically as it pertains to children and adolescents.Monogenic DiabetesDiabetes as a result of a single gene abnormality, or monogenic diabetes, shares clinical overlap with T2D, particularly T2D in youth. There are 3 major subgroups of monogenic diabetes: neonatal diabetes, syndromic diabetes, and maturity-onset diabetes of the young (MODY). Neonatal diabetes presents in infancy, although only a subset of infants develops diabetes in the neonatal period (the first 30 days of life); the majority of patients become symptomatic within the first 6 months of life.20Rubio-Cabezas O. Ellard S. Diabetes mellitus in neonates and infants: genetic heterogeneity, clinical approach to diagnosis, and therapeutic options.Horm Res Paediatr. 2013; 80: 137-146Crossref PubMed Scopus (66) Google Scholar Syndromic diabetes presents with additional extrapancreatic features, typically also in infancy.20Rubio-Cabezas O. Ellard S. Diabetes mellitus in neonates and infants: genetic heterogeneity, clinical approach to diagnosis, and therapeutic options.Horm Res Paediatr. 2013; 80: 137-146Crossref PubMed Scopus (66) Google Scholar MODY is characterized by non–insulin-dependent diabetes diagnosed at a young age (<25 years) demonstrating an autosomal dominant inheritance pattern.21Tattersall R.B. Fajans S.S. A difference between the inheritance of classical juvenile-onset and maturity-onset type diabetes of young people.Diabetes. 1975; 24: 44-53Crossref PubMed Scopus (346) Google Scholar Subtypes of MODY are based on specific genetic defects, with involvement of different genes associated with differences in clinical and physiologic phenotypes.22Hattersley A.T. Maturity-onset diabetes of the young: clinical heterogeneity explained by genetic heterogeneity.Diabet Med. 1998; 15: 15-24Crossref PubMed Scopus (264) Google ScholarMonogenic diabetes can be caused by pathogenic mutations in genes that disrupt glucose sensing, insulin transcription, the potassium–adenosine triphosphate channel that transduces the signal for insulin release, the insulin gene, or pancreatic development. Understanding the genes associated with monogenic forms of diabetes has provided insight into the disease mechanisms of diabetes. Eleven different genes have been identified as causal for MODY in the Online Mendelian Inheritance in Man catalog: HNF4A (MODY 1), GCK (MODY 2), HNF1A (MODY 3), PDX1 (MODY 4), HNF1B (MODY 5), NEUROD1 (MODY 6), CEL (MODY 8), INS (MODY 10), ABCC8 (MODY 12), KCNJ11 (MODY 13), and APPL1 (MODY 14). Note that the genes previously reported as causal for MODY 7, MODY 9, and MODY 11 are absent from this list, owing to the recent proposal to eliminate them from the list of causal MODY genes based on updated genetic evidence.23Laver T.W. Wakeling M.N. Knox O. Colclough K. Wright C.F. Ellard S. 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: 1128-1136Crossref PubMed Scopus (4) Google Scholar Mutations in the HNF4A and HNF1A genes lead to abnormal insulin secretion, and MODY caused by variants in these genes can be effectively managed with oral sulfonylurea therapy.24Pearson E.R. Pruhova S. Tack C.J. Johansen A. Castleden H.A. Lumb P.J. et al.Molecular genetics and phenotypic characteristics of MODY caused by hepatocyte nuclear factor 4alpha mutations in a large European collection.Diabetologia. 2005; 48: 878-885Crossref PubMed Scopus (178) Google Scholar,25Pearson E.R. Starkey B.J. Powell R.J. Gribble F.M. Clark P.M. Hattersley A.T. Genetic cause of hyperglycaemia and response to treatment in diabetes.Lancet. 2003; 362: 1275-1281Abstract Full Text Full Text PDF PubMed Scopus (461) Google Scholar MODY caused by pathogenic variants in GCK, the gene encoding glucokinase, which phosphorylates glucose to glucose-6-phosphate in pancreatic cells and acts as a glucose sensor, is characterized by a mild, stable hyperglycemia with a low risk of complications that commonly does not require any treatment.26Steele A.M. Shields B.M. Wensley K.J. Colclough K. Ellard S. Hattersley A.T. Prevalence of vascular complications among patients with glucokinase mutations and prolonged, mild hyperglycemia.JAMA. 2014; 311: 279-286Crossref PubMed Scopus (200) Google ScholarGiven the clinical overlap between T2D and rarer forms of diabetes, a long-held hypothesis is that the genetic underpinnings of both common and rare forms of diabetes might not be entirely distinct. Multiple studies have shown that MODY affects a small but not insignificant subset of youth with diabetes, including those clinically diagnosed with T2D. The SEARCH for Diabetes in Youth Study published the first systematic study of MODY prevalence in US youth, which reported a 1.2% overall prevalence of MODY.27Pihoker C. Gilliam L.K. Ellard S. Dabelea D. Davis C. Dolan L.M. et al.Prevalence, characteristics and clinical diagnosis of maturity onset diabetes of the young due to mutations in HNF1A, HNF4A, and glucokinase: results from the SEARCH for Diabetes in Youth.J Clin Endocrinol Metab. 2013; 98: 4055-4062Crossref PubMed Scopus (219) Google Scholar A genetic sequencing study of participants in the TODAY study found that 4.5% carried a pathogenic variant in a MODY gene.28Kleinberger J.W. Copeland K.C. Gandica R.G. Haymond M.W. Levitsky L.L. Linder B. et al.Monogenic diabetes in overweight and obese youth diagnosed with type 2 diabetes: the TODAY clinical trial.Genet Med. 2018; 20: 583-590Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar A larger genetic study conducted by the Progress in Diabetes Genetics in Youth (ProDiGY) consortium that included the TODAY cohort, a second cohort recruited by the TODAY researchers for genetic studies, and a subset of the SEARCH for Diabetes in Youth study participants identified a 2.8% incidence of MODY.28Kleinberger J.W. Copeland K.C. Gandica R.G. Haymond M.W. Levitsky L.L. Linder B. et al.Monogenic diabetes in overweight and obese youth diagnosed with type 2 diabetes: the TODAY clinical trial.Genet Med. 2018; 20: 583-590Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar,29Todd J.N. Kleinberger J.W. Zhang H. Srinivasan S. Tollefsen S.E. Levitsky L.L. et al.Monogenic diabetes in youth with presumed type 2 diabetes: results from the Progress in Diabetes Genetics in Youth (ProDiGY) collaboration.Diabetes Care. 2021; 44: 2312-2319Crossref Scopus (10) Google Scholar These studies focused on rare, highly penetrant variants in known MODY genes. In adult studies of T2D genetics, there is increasing overlap of common variant associations and genes associated with monogenic diabetes.30Flannick J. Johansson S. Njølstad P.R. Common and rare forms of diabetes mellitus: towards a continuum of diabetes subtypes.Nat Rev Endocrinol. 2016; 12: 394-406Crossref PubMed Scopus (78) Google Scholar Although such associations have not yet been shown in youth with T2D, it is possible that further examination of rarer variants will find associations along a spectrum of disease risk in genes or pathways relevant to diabetes.Candidate Gene StudiesMany efforts to understand the genetic underpinnings of T2D in children have focused on genetic variants with known associations with glycemic traits or T2D risk in adults, examining whether similar associations exist in youth. Individual variants have been shown to have similar associations in children for both fasting glucose31Barker A. Sharp S.J. Timpson N.J. Bouatia-Naji N. Warrington N.M. Kanoni S. et al.Association of genetic Loci with glucose levels in childhood and adolescence: a meta-analysis of over 6,000 children.Diabetes. 2011; 60: 1805-1812Crossref PubMed Scopus (87) Google Scholar,32Kelliny C. Ekelund U. Andersen L.B. Brage S. Loos R.J. Wareham N.J. et al.Common genetic determinants of glucose homeostasis in healthy children: the European Youth Heart Study.Diabetes. 2009; 58: 2939-2945Crossref PubMed Scopus (50) Google Scholar and the homeostasis model assessment of β cell function.31Barker A. Sharp S.J. Timpson N.J. Bouatia-Naji N. Warrington N.M. Kanoni S. et al.Association of genetic Loci with glucose levels in childhood and adolescence: a meta-analysis of over 6,000 children.Diabetes. 2011; 60: 1805-1812Crossref PubMed Scopus (87) Google Scholar Several T2D risk genes have been associated with youth-onset T2D, including TCF7L2,33Dabelea D. Dolan L.M. D'Agostino Jr., R. Hernandez A.M. McAteer J.B. Hamman R.F. et al.Association testing of TCF7L2 polymorphisms with type 2 diabetes in multi-ethnic youth.Diabetologia. 2011; 54: 535-539Crossref PubMed Scopus (42) Google Scholar,34Miranda-Lora A.L. Cruz M. Molina-Díaz M. Gutiérrez J. Flores-Huerta S. Klünder-Klünder M. Associations of common variants in the SLC16A11, TCF7L2, and ABCA1 genes with pediatric-onset type 2 diabetes and related glycemic traits in families: a case-control and case-parent trio study.Pediatr Diabetes. 2017; 18: 824-831Crossref PubMed Scopus (16) Google Scholar SLC16A11, and ABCA1.34Miranda-Lora A.L. Cruz M. Molina-Díaz M. Gutiérrez J. Flores-Huerta S. Klünder-Klünder M. Associations of common variants in the SLC16A11, TCF7L2, and ABCA1 genes with pediatric-onset type 2 diabetes and related glycemic traits in families: a case-control and case-parent trio study.Pediatr Diabetes. 2017; 18: 824-831Crossref PubMed Scopus (16) Google ScholarGenetic risk scores (GRSs), which allow for the assessment of the aggregate genetic risk of a given trait, have demonstrated association of GRSs constructed from variants associated in adults with glycemic traits and/or T2D risk with fasting glucose and measures of β-cell function,35Carayol J. Hosking J. Pinkney J. Marquis J. Charpagne A. Metairon S. et al.Genetic susceptibility determines β-cell function and fasting glycemia trajectories throughout childhood: a 12-year cohort study (EarlyBird 76).Diabetes Care. 2020; 43: 653-660Crossref PubMed Scopus (9) Google Scholar, 36Giannini C. Dalla Man C. Groop L. Cobelli C. Zhao H. Shaw M.M. et al.Co-occurrence of risk alleles in or near genes modulating insulin secretion predisposes obese youth to prediabetes.Diabetes Care. 2014; 37: 475-482Crossref PubMed Scopus (29) Google Scholar, 37Morandi A. Bonnefond A. Lobbens S. Yengo L. Miraglia Del Giudice E. Grandone A. et al.Associations between type 2 diabetes-related genetic scores and metabolic traits, in obese and normal-weight youths.J Clin Endocrinol Metab. 2016; 101: 4244-4250Crossref PubMed Scopus (7) Google Scholar as well as measures of insulin resistance35Carayol J. Hosking J. Pinkney J. Marquis J. Charpagne A. Metairon S. et al.Genetic susceptibility determines β-cell function and fasting glycemia trajectories throughout childhood: a 12-year cohort study (EarlyBird 76).Diabetes Care. 2020; 43: 653-660Crossref PubMed Scopus (9) Google Scholar,36Giannini C. Dalla Man C. Groop L. Cobelli C. Zhao H. Shaw M.M. et al.Co-occurrence of risk alleles in or near genes modulating insulin secretion predisposes obese youth to prediabetes.Diabetes Care. 2014; 37: 475-482Crossref PubMed Scopus (29) Google Scholar,38Graae A.S. Hollensted M. Kloppenborg J.T. Mahendran Y. Schnurr T.M. Appel E.V. et al.An adult-based insulin resistance genetic risk score associates with insulin resistance, metabolic traits and altered fat distribution in Danish children and adolescents who are overweight or obese.Diabetologia. 2018; 61: 1769-1779Crossref PubMed Scopus (9) Google Scholar in youth. Two studies have examined the ability of GRSs to identify children at risk of progressing to T2D; even though the scores were shown to be associated with T2D risk,36Giannini C. Dalla Man C. Groop L. Cobelli C. Zhao H. Shaw M.M. et al.Co-occurrence of risk alleles in or near genes modulating insulin secretion predisposes obese youth to prediabetes.Diabetes Care. 2014; 37: 475-482Crossref PubMed Scopus (29) Google Scholar,39Miranda-Lora A.L. Vilchis-Gil J. Juárez-Comboni D.B. Cruz M. Klünder-Klünder M. A genetic risk score improves the prediction of type 2 diabetes mellitus in Mexican youths but has lower predictive utility compared with non-genetic factors.Front Endocrinol (Lausanne). 2021; 12: 647864Crossref PubMed Scopus (4) Google Scholar in one of the studies clinical factors such as body mass index (BMI) and family history of T2D had higher predictive utility.34Miranda-Lora A.L. Cruz M. Molina-Díaz M. Gutiérrez J. Flores-Huerta S. Klünder-Klünder M. Associations of common variants in the SLC16A11, TCF7L2, and ABCA1 genes with pediatric-onset type 2 diabetes and related glycemic traits in families: a case-control and case-parent trio study.Pediatr Diabetes. 2017; 18: 824-831Crossref PubMed Scopus (16) Google ScholarGenome-Wide Association StudiesSince the first genome-wide association study (GWAS) for T2D in adults was published in 2007,40Sladek R. Rocheleau G. Rung J. Dina C. Shen L. Serre D. et al.A genome-wide association study identifies novel risk loci for type 2 diabetes.Nature. 2007; 445: 881-885Crossref PubMed Scopus (2352) Google Scholar there has been an explosion of genetic discoveries related to adult T2D with extremely well-powered studies and advanced analytic techniques. At the time of this publication, >400 variants have been associated with T2D in adults.41Mahajan A. Taliun D. Thurner M. Robertson N.R. Torres J.M. Rayner N.W. et al.Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps.Nat Genet. 2018; 50: 1505-1513Crossref PubMed Scopus (671) Google Scholar In comparison, large scale studies of pediatric T2D have not been conducted, largely due to limited sample sizes. To address this gap, we and colleagues formed the ProDiGY Consortium, which is a collaboration of 3 research groups: the TODAY study,42Zeitler P. Epstein L. Grey M. Hirst K. Kaufman F. et Study for type 2 diabetes in adolescents and a study of the of metformin or in combination with or in adolescents with type 2 Diabetes. 2007; PubMed Scopus Google Scholar SEARCH for Diabetes in Study for Diabetes in a study of the incidence and of diabetes mellitus in Clin Full Text Full Text PDF PubMed Scopus Google Scholar and the 2 Diabetes Genetic by in C. J. T.M. A. K.J. et al.The genetic of type 2 diabetes.Nature. 2016; PubMed Scopus Google Scholar The ProDiGY study is a to understanding of the genetics of T2D in youth by the sample and phenotypic data of 2 pediatric T2D studies with the genetic and of a adult diabetes genetics we conducted the first for T2D in youth to identify genetic variants specifically to youth-onset S. L. J. Divers J. S. S. et al.The first genome-wide association study for type 2 diabetes in the Progress in Diabetes Genetics in Youth (ProDiGY) 2021; PubMed Scopus (10) Google Scholar our genetic in youth with T2D who were for pancreatic and adult years and identified genome-wide including the novel in with an of for T2D, that of the risk a of T2D compared with the A The 6 loci were previously identified in adults and included TCF7L2, and S. L. J. Divers J. S. S. et al.The first genome-wide association study for type 2 diabetes in the Progress in Diabetes Genetics in Youth (ProDiGY) 2021; PubMed Scopus (10) Google the of our ProDiGY our hypothesis was that genetic were in youth with T2D compared with adults, given the T2D with to early age of To this we constructed GRSs in ProDiGY from known T2D variants identified in A. Zhang K.J. T. et meta-analysis insight into the genetic of type 2 diabetes Genet. 2014; PubMed Scopus Google Scholar of the association of the risk score between youth and adult and a higher for T2D in the youth compared with the adult in with our S. L. J. Divers J. S. S. et al.The first genome-wide association study for type 2 diabetes in the Progress in Diabetes Genetics in Youth (ProDiGY) 2021; PubMed Scopus (10) Google Scholar the efforts of the ProDiGY consortium have provided insight into the genetic of T2D in youth and have shown that the genetic of T2D in youth largely with that in adults but with a aggregate genetic risk studies of genes are to understand how the identified genetic variants disease the between and genetic factors are also to T2D risk in of Genetics in has been in our understanding of the genetics of T2D in youth to in sequencing and such as ProDiGY to sample sizes. Here we the of genetics as it pertains to pediatric T2D is a disease of from both environmental and genetic as well as of insulin resistance and β-cell among The of in MODY 3 is a of how genetics can be to disease and Although not as genetics also can be to for the more common of T2D. A approach has been to the heterogeneity of T2D with of loci mechanisms of disease based on β cell insulin resistance, and fat J. M. S. J.B. J. et 2 diabetes genetic loci by associations to disease mechanisms and a Med. 2018; 15: PubMed Scopus Google D. R.B. A. R. M. et association differences of Genet. 2021; PubMed Scopus Google Scholar These efforts to to with the of clinical and the risk of complications in the The of using genetic data to disease is that it over an and can be even a particularly for children who have T2D from the Diabetes Association youth with obesity for T2D based on the presence of additional risk including a family history of T2D, history of diabetes, and associated with insulin resistance, such as Diabetes and of in Care. 2021; 44: PubMed Scopus Google Scholar Although these allow to identify youth diabetes it is not which of these youth will on to T2D. In there is or between clinical as body mass fasting insulin or and the to the early days of T2D studies that a risk score for T2D in adults does not clinical of but to clinical risk genetic may predictive particularly for of adults in risk such as glucose might not have T. B. T. et al.Common genetic variants the from clinically of fasting glucose 2012; PubMed Scopus Google Scholar a risk score of 1 variants and that the of the distribution can identify adults with a to in T2D the of the as the the reported predictive was and the predictive was T. A. et of a risk score for type 2 diabetes in 2022; Scopus Google Scholar Although the current clinical utility of in the more scores from will to improve the predictive of these into can related to T2D with the of pathways related to the genetic the in TCF7L2, which has one of the known for common variants in both youth and adults with D. Dolan L.M. D'Agostino Jr., R. Hernandez A.M. McAteer J.B. Hamman R.F. et al.Association testing of TCF7L2 polymorphisms with type 2 diabetes in multi-ethnic youth.Diabetologia. 2011; 54: 535-539Crossref PubMed Scopus (42) Google R. Rocheleau G. Rung J. Dina C. Shen L. Serre D. et al.A genome-wide association study identifies novel risk loci for type 2 diabetes.Nature. 2007; 445: 881-885Crossref PubMed Scopus (2352) Google S. L. J.

Type 2 Diabetes in Children and Adolescents

Maturity-onset diabetes of the young (MODY) is a monogenic form of diabetes characterised by early-onset diabetes and inherited in an autosomal dominant manner. MODY results from heterozygous mutations in genes important for pancreatic β-cell development or function. The objective was to identify the most common and rarest types of MODY amongst our cases with genetically confirmed MODY diagnosis, to evaluate clinical and laboratory features and treatment regimens. The epidemiological, auxological, and laboratory data, genetic analysis results and treatment regimens of patients diagnosed with MODY were retrospectively evaluated. Of the 44 cases included, 27 (61.4%) were male and the median age at diagnosis was 10.07 (1-16.8) years. There was a family history of diabetes in 42 (95.5%) cases. The distribution of gene variants was: 25 (55.8%) glucokinase (GCK), 4 (9.1%) hepatocyte nuclear factor-4-alpha, 4 (9.1%) carboxyl ester lipase, 2 (4.5%) B lymphocyte kinase, 4 (9.1%) ATP-binding cassette subfamily C member 8, 2 (4.5%) Kruppel-like factor 11, 1 (2.3%) insulin (INS), 1 (2.3%) potassium channel, inwardly rectifying, subfamily J member 11, and 1 (2.3%) adaptor protein, phosphotyrosine interaction, pH domain, and leucine zipper containing 1. At presentation, 23 (52.3%) of the cases had incidental hyperglycemia while 14 (31.8%) had polyuria and polydipsia. Diabetic ketoacidosis was detected in 4 (9.1%) and ketonemia in 3 (6.9%). At least one of the diabetes autoantibodies (anti-glutamate acid decarboxylase, anti-islet cell antibodies, anti-insulin autoantibodies) was detected in 11 (25%) cases, of which 7/11 were islet antibodies, and 5 patients (11%) had two autoantibodies positive simultaneously. In terms of treatment, 26 (59%) received diet and lifestyle changes only, 18 (41%) received oral antidiabetic agents and/or insulin, and 6 (13.6%) received both oral antidiabetic agents and insulin. The most common type of MODY in our cohort was GCK-MODY. Although MODY is generally known as an autoantibodynegative type of diabetes, autoantibody positivity was detected in 11 of 44 cases (25%) in the present study.

Type 2 Diabetes in Children and Adolescents.

Heterozygous pathogenic variants in HNF4A gene cause maturity-onset diabetes of the young type 1 (MODY1). The mutation carriers for MODY1 have been reported to be relatively rare, in contrast to the most frequently reported forms of MODY2 and MODY3. Whole exome sequencing (WES) and Sanger sequencing were performed for genetic analysis of MODY pedigrees. Tertiary structures of the mutated proteins were predicted using PyMOL software. Three heterozygous missense mutations in the HNF4A gene, I159T, W179C, and D260N, were identified in the probands of three unrelated MODY families using WES, one of which (W179C) was novel. Cascade genetic screening revealed that the mutations co-segregated with hyperglycemic phenotypes in their families. The molecular diagnosis of MODY1 has partly transformed its management in clinical practice and improved glycemic control. The proband in family A successfully converted to sulfonylureas and achieved good glycemic control. Proband B responded well to metformin combined with diet therapy because of his higher body mass index (BMI). The proband in family C, with paternal-derived mutations, had markedly defective pancreatic β-cell function due to the superposition effect of T2DM susceptibility genes from the maternal grandfather, and he is currently treated with insulin. In silico analysis using PyMOL showed that the I159T and D260N mutations altered polar interactions with the surrounding residues, and W179C resulted in a smaller side chain. We identified three heterozygous missense mutations of HNF4A from Chinese MODY families. Structural alterations in these mutations may lead to defects in protein function, further contributing to the hyperglycemic phenotype of mutation carriers.

Maturity-onset diabetes of the young (MODY) and congenital hyperinsulinism (CHI) are monogenic disorders of glucose-stimulated insulin secretion. MODY is the commonest form of monogenic diabetes and results from a heterozygous mutation in one of thirteen identified genes. It is estimated that up to 90% of cases of MODY are not diagnosed, possibly due to the insufficient awareness of or access to genetic screening. CHI is the commonest cause of persistent hypoglycemia in infancy and childhood, for which there are ten identified genes (mutation-positive disease found in 45% of all CHI, and 88% of diazoxide-unresponsive cases).Genetic confirmation of MODY and CHI traditionally involved Sanger sequencing of each exon of each gene individually; however, the development of massively parallel sequencing (MPS) allows simultaneous sequencing of multiple target regions efficiently and cost-effectively. This thesis assessed two forms of MPS - whole exome sequencing and targeted sequencing, in population and small family cohorts.An entire paediatric diabetes clinic underwent targeted MPS for MODY genes, which showed the prevalence of pathogenic/likely pathogenic MODY variants to be 2.1%. Based on these results, a cost-effectiveness analysis was performed, demonstrating that routine MPS screening for MODY in all paediatric cases with presumed type 1 diabetes was cost-saving. The utility of WES was evaluated in MODY and CHI in a proof-of-concept study. Subjects with known mutations in MODY and CHI genes were re-sequenced using two “off-the-shelf” WES capture technologies. All mutations were confirmed; however, the study showed the importance of careful selection of appropriate capture technology to ensure targeting of relevant genes and the use of bioinformatics tools appropriate to mutation type. Seven probands diagnosed with MODY but without a previously identified mutation were also assessed using WES. Three novel variants in known MODY genes were identified by WES, which variants segregated with diabetes in the families. A potential novel MODY gene was also identified through sequencing of one extended family. Six probands with CHI but without a known mutation were also sequenced. Two probands and their affected family members had the same variant in a potential novel CHI gene. MPS is an extremely useful addition to the diagnostic workup for paediatric cases of diabetes overall, in addition to its utility in screening clinically diagnosed MODY/CHI cases. Additionally, MPS can lead to novel gene identification for these conditions.

Diabetes is a common disorder with a heterogeneous clinical presentation and an enormous burden on health care worldwide. About 1-6% of patients with diabetes suffer from maturity-onset diabetes of the young (MODY), the most common form of monogenic diabetes with autosomal dominant inheritance. MODY is genetically and clinically heterogeneous and caused by genetic variations in pancreatic β-cell development and insulin secretion. We report here new findings from targeted next-generation sequencing (NGS) of 13 MODY-related genes. A sample of 22 unrelated pediatric patients with MODY and 13 unrelated healthy controls were recruited from a Turkish population. Targeted NGS was performed with Miseq 4000 (Illumina) to identify genetic variations in 13 MODY-related genes: HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, ABCC8, and KCNJ11. The NGS data were analyzed adhering to the Genome Analysis ToolKit (GATK) best practices pipeline, and variant filtering and annotation were performed. In the patient sample, we identified 43 MODY-specific genetic variations that were not present in the control group, including 11 missense mutations and 4 synonymous mutations. Importantly, and to the best of our knowledge, the missense mutations NEUROD1 p.D202E, KFL11 p.R461Q, BLK p.G248R, and KCNJ11 p.S385F were first associated with MODY in the present study. These findings contribute to the worldwide knowledge base on MODY and molecular correlates of clinical heterogeneity in monogenic childhood diabetes. Further comparative population genetics and functional genomics studies are called for, with an eye to discovery of novel diagnostics and personalized medicine in MODY. Because MODY is often misdiagnosed as type 1 or type 2 diabetes mellitus, advances in MODY diagnostics with NGS stand to benefit diabetes overall clinical care as well.