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Ding Y, Zhang Q, Gao S, Li J, Chang G, Wang Y, Wang L, Li X, Chen Y, Yao RE, Yu T, Li N, Lou D, Wang X. Focusing on Rare Variants Related to Maturity-Onset Diabetes of the Young in Children. Pediatr Diabetes 2025; 2025:8155443. [PMID: 40303944 PMCID: PMC12017003 DOI: 10.1155/pedi/8155443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 01/08/2025] [Indexed: 05/02/2025] Open
Abstract
Background: In this study, we analysed the clinical and genetic characteristics and follow-up data of patients with maturity-onset diabetes of the young (MODY). Methods: From January 2015 to December 2022, patients with persistent hyperglycaemia suspected of having monogenic diabetes or diabetes syndrome were recruited, and next-generation sequencing (NGS) was performed at the Shanghai Children's Medical Center. Patients' clinical and laboratory findings were recorded preceding follow-ups. Candidate variants were verified using Sanger sequencing. Variant pathogenicity was evaluated according to the American College of Medical Genetics and Genomics (ACMG) guidelines. Results: Genetic testing was performed in 175 children. MODY-related pathogenic or likely pathogenic gene variants were identified in 30 patients from different families. Of these, 11 were diagnosed with GCK-MODY (36.7%), six with INS-MODY (20%), five with HNF1A-MODY (16.7%), five with ABCC8-MODY (16.7%), two with HNF1B-MODY (6.7%) and one with HNF4A-MODY (3.3%). There was one shift variant and seven splice-site variants, and the rest were missense variants. We discovered six novel variants. Of the 30 patients, 63.3% had a family history of diabetes, 13.3% had diabetic ketoacidosis (DKA), and 16.7% had positive diabetes-associated autoantibodies. The diabetes phenotype of patients with the INS variant was similar to that of patients with type 1 diabetes. All patients, including those having positive autoantibodies, required long-term insulin therapy during follow-ups. Four patients with the ABCC8 variant were unable to switch to oral sulfonylurea therapy and continued insulin therapy. Conclusion: Genetic testing is helpful for the precise diagnosis and treatment of patients with MODY, including those with DKA history and positive diabetes autoantibody. GCK-MODY is the most common type of MODY, and patients with INS variant account for a relatively large proportion of MODY cases in our cohort.
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Affiliation(s)
- Yu Ding
- Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
| | - Qianwen Zhang
- Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
| | - Shiyang Gao
- Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
| | - Juan Li
- Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
| | - Guoying Chang
- Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
| | - Yirou Wang
- Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
| | - Libo Wang
- Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
| | - Xin Li
- Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
| | - Yao Chen
- Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
| | - Ru-en Yao
- Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
| | - Tingting Yu
- Department of Medical Genetics and Molecular Diagnostic Laboratory, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
| | - Niu Li
- Department of Reproductive Genetics, International Peace Maternity and Child Health Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200030, China
| | - Dan Lou
- Department of Pediatrics, The First Affiliated Hospital of Henan University of Science and Technology, Henan University of Science and Technology, Luoyang 471000, China
| | - Xiumin Wang
- Department of Endocrinology and Metabolism, Shanghai Children's Medical Center, Shanghai Jiaotong University School of Medicine, Shanghai 200127, China
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McCullough ME, Letourneau-Freiberg LR, Naylor RN, Greeley SAW, Broome DT, Tosur M, Kreienkamp RJ, Cobry E, Rasouli N, Pollin TI, Udler MS, Billings LK, Desouza C, Evans-Molina C, Birz S, Furner B, Watkins M, Ott K, Volchenboum SL, Philipson LH. Advancing Monogenic Diabetes Research and Clinical Care by Creating a Data Commons: The Precision Diabetes Consortium (PREDICT). J Diabetes Sci Technol 2025:19322968241310896. [PMID: 39781649 PMCID: PMC11713946 DOI: 10.1177/19322968241310896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/12/2025]
Abstract
Monogenic diabetes mellitus (MDM) is a group of relatively rare disorders caused by pathogenic variants in key genes that result in hyperglycemia. Lack of identified cases, along with absent data standards, and limited collaboration across institutions have hindered research progress. To address this, the UChicago Monogenic Diabetes Registry (UCMDMR) and UChicago Data for the Common Good (D4CG) created a national consortium of MDM research institutions called the PREcision DIabetes ConsorTium (PREDICT). Following the D4CG model, PREDICT has successfully established a multicenter MDM data commons. PREDICT has created a consensus data dictionary that will be utilized to address critical gaps in understanding of these rare types of diabetes. This approach may be useful for other rare conditions that would benefit from access to harmonized pooled data.
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Affiliation(s)
| | | | - Rochelle N. Naylor
- Department of Medicine, The University of Chicago, Chicago, IL, USA
- Department of Pediatrics, The University of Chicago, Chicago, IL, USA
| | - Siri Atma W. Greeley
- Department of Medicine, The University of Chicago, Chicago, IL, USA
- Department of Pediatrics, The University of Chicago, Chicago, IL, USA
| | | | - Mustafa Tosur
- Division of Diabetes and Endocrinology, Department of Pediatrics, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, USA
- Children’s Nutrition Research Center, U.S. Department of Agriculture, Agricultural Research Service, Houston, TX, USA
| | | | - Erin Cobry
- Barbara Davis Center for Diabetes, Anschutz Medical Campus, University of Colorado, Aurora, CO, USA
| | - Neda Rasouli
- Anschutz Medical Campus, University of Colorado, Aurora, CO, USA
| | - Toni I. Pollin
- University of Maryland School of Medicine, Baltimore, MD, USA
| | | | - Liana K. Billings
- Division of Endocrinology, Endeavor Health, NorthShore Hospitals, Evanston, IL, USA
- Department of Medicine, Pritzker School of Medicine, The University of Chicago, Chicago, IL, USA
| | - Cyrus Desouza
- University of Nebraska Medical Center, Omaha, NE, USA
| | | | - Suzi Birz
- Department of Pediatrics, The University of Chicago, Chicago, IL, USA
| | - Brian Furner
- Department of Pediatrics, The University of Chicago, Chicago, IL, USA
| | - Michael Watkins
- Department of Pediatrics, The University of Chicago, Chicago, IL, USA
| | - Kaitlyn Ott
- Department of Pediatrics, The University of Chicago, Chicago, IL, USA
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Lanzinger S, Laubner K, Warncke K, Mader JK, Kummer S, Boettcher C, Biester T, Galler A, Klose D, Holl RW. Clinical characteristics, treatment, and treatment switch after molecular-genetic classification in individuals with maturity-onset diabetes of the young: Insights from the multicenter real-world DPV registry. J Diabetes 2024; 16:e70028. [PMID: 39511990 PMCID: PMC11544032 DOI: 10.1111/1753-0407.70028] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2024] [Revised: 08/30/2024] [Accepted: 10/20/2024] [Indexed: 11/15/2024] Open
Abstract
BACKGROUND Individuals with maturity-onset diabetes of the young (MODY) are often misdiagnosed as type 1 or type 2 diabetes and receive inappropriate care. We aimed to investigate the characteristics and treatment of all MODY types in a multicenter, real-world setting. METHODS Individuals with MODY from the diabetes prospective follow-up (DPV) registry were studied. We compared clinical parameters during the first year of diabetes and the most recent treatment year after MODY diagnosis. RESULTS A total of 1640 individuals were identified with GCK-MODY (n = 941) and HNF1A-MODY (n = 417) as the most frequent types. Among these, 912 individuals were available with information during the first and the most recent treatment year (median duration of follow-up: 4.2 years [2.6-6.6]). Positive beta cell autoantibodies were present in 20.6% (15.2% IAA). Median age at diagnosis ranged from 9.9 years in GCK-MODY (Q1-Q3: 6.2-13.1 years) and INS-MODY (2.7-13.7 years) to 14.3 years (5.0-17.1) in KCNJ11-MODY. Frequency of oral antidiabetic agents (OAD) use increased and insulin decreased in HNF4A-MODY (OAD: 18% to 39%, insulin: 34% to 23%) and in HNF1A-MODY (OAD: 18% to 31%, insulin: 35% to 25%). ABCC8-MODY was characterized by a decrement in nonpharmacological treatment (26% to 16%) and "insulin only" treatment (53% to 42%), while the proportion of individuals treated with OAD but no insulin increased from 0% to 21%. CONCLUSIONS Our results indicate that some teams caring for individuals with MODY are hesitant with regard to current recommendations. Registries are an essential source of information and provide a basis for discussing treatment guidelines for MODY.
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Affiliation(s)
- Stefanie Lanzinger
- Institute of Epidemiology and Medical Biometry, CAQM, Ulm University, Ulm, Germany
- Munich-Neuherberg, German Center for Diabetes Research (DZD), Munich, Germany
| | - Katharina Laubner
- Division of Endocrinology and Diabetology, Department of Medicine II, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg im Breisgau, Germany
| | - Katharina Warncke
- Department of Pediatrics, Kinderklinik München Schwabing, Technical University of Munich School of Medicine, Munich, Germany
| | - Julia K Mader
- Division of Endocrinology and Diabetology, Department of Internal Medicine, Medical University of Graz, Graz, Austria
| | - Sebastian Kummer
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty and University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Claudia Boettcher
- Paediatric Endocrinology and Diabetology, University Children's Hospital, University of Bern, Bern, Switzerland
| | - Torben Biester
- AUF DER BULT, Diabetes-Center for Children and Adolescents, Hannover, Germany
| | - Angela Galler
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Sozialpädiatrisches Zentrum, Paediatric Diabetology, Berlin, Germany
| | - Daniela Klose
- Division of Pediatric Endocrinology und Diabetes, Department of Pediatrics, University of Heidelberg, Heidelberg, Germany
| | - Reinhard W Holl
- Institute of Epidemiology and Medical Biometry, CAQM, Ulm University, Ulm, Germany
- Munich-Neuherberg, German Center for Diabetes Research (DZD), Munich, Germany
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Serbis A, Kantza E, Siomou E, Galli-Tsinopoulou A, Kanaka-Gantenbein C, Tigas S. Monogenic Defects of Beta Cell Function: From Clinical Suspicion to Genetic Diagnosis and Management of Rare Types of Diabetes. Int J Mol Sci 2024; 25:10501. [PMID: 39408828 PMCID: PMC11476815 DOI: 10.3390/ijms251910501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2024] [Revised: 09/25/2024] [Accepted: 09/27/2024] [Indexed: 10/20/2024] Open
Abstract
Monogenic defects of beta cell function refer to a group of rare disorders that are characterized by early-onset diabetes mellitus due to a single gene mutation affecting insulin secretion. It accounts for up to 5% of all pediatric diabetes cases and includes transient or permanent neonatal diabetes, maturity-onset diabetes of the young (MODY), and various syndromes associated with diabetes. Causative mutations have been identified in genes regulating the development or function of the pancreatic beta cells responsible for normal insulin production and/or release. To date, more than 40 monogenic diabetes subtypes have been described, with those caused by mutations in HNF1A and GCK genes being the most prevalent. Despite being caused by a single gene mutation, each type of monogenic diabetes, especially MODY, can appear with various clinical phenotypes, even among members of the same family. This clinical heterogeneity, its rarity, and the fact that it shares some features with more common types of diabetes, can make the clinical diagnosis of monogenic diabetes rather challenging. Indeed, several cases of MODY or syndromic diabetes are accurately diagnosed in adulthood, after having been mislabeled as type 1 or type 2 diabetes. The recent widespread use of more reliable sequencing techniques has improved monogenic diabetes diagnosis, which is important to guide appropriate treatment and genetic counselling. The current review aims to summarize the latest knowledge on the clinical presentation, genetic confirmation, and therapeutic approach of the various forms of monogenic defects of beta cell function, using three imaginary clinical scenarios and highlighting clinical and laboratory features that can guide the clinician in reaching the correct diagnosis.
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Affiliation(s)
- Anastasios Serbis
- Department of Pediatrics, University of Ioannina, 45110 Ioannina, Greece; (E.K.); (E.S.)
- Department of Endocrinology & Diabetes Center, University of Ioannina, 45110 Ioannina, Greece;
- 2nd Department of Pediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, AHEPA University General Hospital, 54636 Thessaloniki, Greece;
| | - Evanthia Kantza
- Department of Pediatrics, University of Ioannina, 45110 Ioannina, Greece; (E.K.); (E.S.)
| | - Ekaterini Siomou
- Department of Pediatrics, University of Ioannina, 45110 Ioannina, Greece; (E.K.); (E.S.)
| | - Assimina Galli-Tsinopoulou
- 2nd Department of Pediatrics, School of Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, AHEPA University General Hospital, 54636 Thessaloniki, Greece;
| | - Christina Kanaka-Gantenbein
- Division of Endocrinology, Diabetes and Metabolism and Aghia Sophia ENDO-ERN Center for Rare Pediatric Endocrine Disorders, First Department of Pediatrics, Medical School, Aghia Sophia Children’s Hospital, National and Kapodistrian University of Athens, 11527 Athens, Greece;
| | - Stelios Tigas
- Department of Endocrinology & Diabetes Center, University of Ioannina, 45110 Ioannina, Greece;
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Özsu E, Çetinkaya S, Bolu S, Hatipoğlu N, Erdeve ŞS, Evliyaoğlu O, Baş F, Çayır A, Dündar İ, Akbaş ED, Uçaktürk SA, Berberoğlu M, Şıklar Z, Özalkak Ş, Şahin NM, Keskin M, Şiraz ÜG, Turan H, Öztürk AP, Mengen E, Sağsak E, Dursun F, Akyürek N, Güneş SO, Aycan Z. Clinical and Laboratory Characteristics of MODY Cases, Genetic Mutation Spectrum and Phenotype-genotype Relationship. J Clin Res Pediatr Endocrinol 2024; 16:297-305. [PMID: 38665000 PMCID: PMC11590772 DOI: 10.4274/jcrpe.galenos.2024.2023-10-16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2023] [Accepted: 03/25/2024] [Indexed: 09/06/2024] Open
Abstract
Objective Maturity onset diabetes of the young (MODY) occurs due to mutations in genes involved in pancreatic beta cell function and insulin secretion, has heterogeneous clinical and laboratory features, and account for 1-5% of all diabetes cases. The prevalence and distribution of MODY subtypes vary between countries. The aim of this study was to evaluate the clinical and laboratory characteristics, mutation distribution, and phenotype-genotype relationship in a large case series of pediatric Turkish patients genetically diagnosed with MODY. Methods MODY cases from 14 different pediatric endocrinology departments were included. Diagnosis, treatment, follow-up data, and results of genetic analysis were evaluated. Results A total of 224 patients were included, of whom 101 (45%) were female, and the mean age at diagnosis was 9.4±4.1 years. Gene variant distribution was: 146 (65%) GCK; 43 (19%) HNF1A; 8 (3.6%) HNF4A, 8 (3.6%) KLF11 and 7 (3.1%) HNF1B. The remaining 12 variants were: PDX (n=1), NEUROD1 (n=3), CEL (n=1), INS (n=3), ABCC8 (n= 3) and KJNC11 (n=1). Of the cases, 197 (87.9%) were diagnosed with incidental hyperglycemia, 16 with ketosis (7%) and 7 (3%) with diabetic ketoacidosis (DKA), while 30% presented with classical symptoms of diabetes. Two-hundred (89%) had a family history of diabetes. Anti-GAD antibody was detected in 13 cases, anti-islet antibody in eight and anti-insulin antibody in four. Obesity was present in 16. Distribution of therapy was: 158 (71%) diet only; 23 (11%) intensive insulin treatment; 17 (7.6%) sulfonylureas; 10 (4.5%) metformin; and 6 (2.7%) insulin and oral anti-diabetic treatment. Conclusion This was the largest genetically diagnosed series from Turkey. The most common gene variants were GCK and HNF1A with much lower proportions for other MODY types. Hyperglycemia was the most common presenting symptom while 11% of patients had diabetes-associated autoantibodies and 7% were obese. The majority of patients received dietary management only.
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Affiliation(s)
- Elif Özsu
- Ankara University Faculty of Medicine, Department of Pediatric Endocrinology, Ankara, Turkey
| | - Semra Çetinkaya
- Dr. Sami Ulus Obstetrics and Gynecology, Pediatric Health and Disease Training and Research Hospital, Clinic of Pediatric Endocrinology, Ankara, Turkey
| | - Semih Bolu
- Adıyaman Training and Research Hospital, Clinic of Pediatric Endocrinology, Adıyaman, Turkey
| | - Nihal Hatipoğlu
- Erciyes University Faculty of Medicine, Department of Pediatric Endocrinology, Kayseri, Turkey
| | - Şenay Savaş Erdeve
- Dr. Sami Ulus Obstetrics and Gynecology, Pediatric Health and Disease Training and Research Hospital, Clinic of Pediatric Endocrinology, Ankara, Turkey
| | - Olcay Evliyaoğlu
- İstanbul University Cerrahpaşa-Cerrahpaşa Faculty of Medicine, Department of Pediatric Endocrinology, İstanbul, Turkey
| | - Firdevs Baş
- İstanbul University, İstanbul Faculty of Medicine, Department of Pediatric Endocrinology, İstanbul, Turkey
| | - Atilla Çayır
- Erzurum Regional Training and Research Hospital, Clinic of Pediatric Endocrinology, Erzurum, Turkey
| | - İsmail Dündar
- Malatya Training and Research Hospital, Clinic of Pediatric Endocrinology, Malatya, Turkey
| | - Emine Demet Akbaş
- Adana Training and Research Hospital, Clinic of Pediatric Endocrinology, Adana, Turkey
| | - Seyid Ahmet Uçaktürk
- Adana Training and Research Hospital, Clinic of Pediatric Endocrinology, Adana, Turkey
| | - Merih Berberoğlu
- Ankara University Faculty of Medicine, Department of Pediatric Endocrinology, Ankara, Turkey
| | - Zeynep Şıklar
- Ankara University Faculty of Medicine, Department of Pediatric Endocrinology, Ankara, Turkey
| | - Şervan Özalkak
- Dr. Sami Ulus Obstetrics and Gynecology, Pediatric Health and Disease Training and Research Hospital, Clinic of Pediatric Endocrinology, Ankara, Turkey
| | - Nursel Muratoğlu Şahin
- Dr. Sami Ulus Obstetrics and Gynecology, Pediatric Health and Disease Training and Research Hospital, Clinic of Pediatric Endocrinology, Ankara, Turkey
| | - Melikşah Keskin
- Dr. Sami Ulus Obstetrics and Gynecology, Pediatric Health and Disease Training and Research Hospital, Clinic of Pediatric Endocrinology, Ankara, Turkey
| | - Ülkü Gül Şiraz
- Erciyes University Faculty of Medicine, Department of Pediatric Endocrinology, Kayseri, Turkey
| | - Hande Turan
- İstanbul University Cerrahpaşa-Cerrahpaşa Faculty of Medicine, Department of Pediatric Endocrinology, İstanbul, Turkey
| | - Ayşe Pınar Öztürk
- İstanbul University, İstanbul Faculty of Medicine, Department of Pediatric Endocrinology, İstanbul, Turkey
| | - Eda Mengen
- Çukurova University Faculty of Medicine, Department of Pediatric Endocrinology, Adana, Turkey
| | - Elif Sağsak
- Yeditepe University Faculty of Medicine, Department of Pediatric Endocrinology İstanbul, Turkey
| | - Fatma Dursun
- Ümraniye Training and Research Hospital, Clinic of Pediatric Endocrinology, İstanbul, Turkey
| | - Nesibe Akyürek
- Başkent University, Konya Training and Research Hospital, Clinic of Pediatric Endocrinology, Konya, Turkey
| | - Sevinç Odabaşı Güneş
- Gülhane Training and Research Hospital, Clinic of Pediatric Endocrinology, Ankara, Turkey
| | - Zehra Aycan
- Ankara University Faculty of Medicine, Department of Pediatric Endocrinology, Ankara, Turkey
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Peixoto-Barbosa R, Calliari LE, Crispim F, Moisés RS, Dib SA, Reis AF, Giuffrida FMA. Clinical screening for GCK-MODY in 2,989 patients from the Brazilian Monogenic Diabetes Study Group (BRASMOD) and the Brazilian Type 1 Diabetes Study Group (BrazDiab1SG). ARCHIVES OF ENDOCRINOLOGY AND METABOLISM 2024; 68:e230314. [PMID: 39420902 PMCID: PMC11326741 DOI: 10.20945/2359-4292-2023-0314] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Accepted: 03/03/2024] [Indexed: 10/19/2024]
Abstract
Objectives To evaluate the accuracy of routinely available parameters in screening for GCK maturity-onset diabetes of the young (MODY), leveraging data from two large cohorts - one of patients with GCK-MODY and the other of patients with type 1 diabetes (T1D). Materials and methods The study included 2,687 patients with T1D, 202 patients with clinical features of MODY but without associated genetic variants (NoVar), and 100 patients with GCK-MODY (GCK). Area under the receiver-operating characteristic curve (ROC-AUC) analyses were used to assess the performance of each parameter - both alone and incorporated into regression models - in discriminating between groups. Results The best parameter discriminating between GCK-MODY and T1D was a multivariable model comprising glycated hemoglobin (HbA1c), fasting plasma glucose, age at diagnosis, hypertension, microvascular complications, previous diabetic ketoacidosis, and family history of diabetes. This model had a ROC-AUC value of 0.980 (95% confidence interval [CI] 0.974-0.985) and positive (PPV) and negative (NPV) predictive values of 43.74% and 100%, respectively. The best model discriminating between GCK and NoVar included HbA1c, age at diagnosis, hypertension, and triglycerides and had a ROC-AUC value of 0.850 (95% CI 0.783-0.916), PPV of 88.36%, and NPV of 97.7%; however, this model was not significantly different from the others. A novel GCK variant was also described in one individual with MODY (7-44192948-T-C, p.Ser54Gly), which showed evidence of pathogenicity on in silico prediction tools. Conclusions This study identified a highly accurate (98%) composite model for differentiating GCK-MODY and T1D. This model may help clinicians select patients for genetic evaluation of monogenic diabetes, enabling them to implement correct treatment without overusing limited resources.
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Affiliation(s)
- Renata Peixoto-Barbosa
- Universidade Federal de São PauloSão PauloSPBrasil Disciplina de Endocrinologia, Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brasil
- Departamento de Ciências da VidaUniversidade do Estado da BahiaSalvadorBABrasil Departamento de Ciências da Vida, Universidade do Estado da Bahia (Uneb), Salvador, BA, Brasil
| | - Luis Eduardo Calliari
- Departamento de PediatriaFaculdade de Ciências MédicasSanta Casa de Misericórdia de São PauloSão PauloSPBrasil Departamento de Pediatria, Faculdade de Ciências Médicas da Santa Casa de Misericórdia de São Paulo, São Paulo, SP, Brasil
| | - Felipe Crispim
- Universidade Federal de São PauloSão PauloSPBrasil Disciplina de Endocrinologia, Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brasil
| | - Regina S. Moisés
- Universidade Federal de São PauloSão PauloSPBrasil Disciplina de Endocrinologia, Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brasil
| | - Sergio A. Dib
- Universidade Federal de São PauloSão PauloSPBrasil Disciplina de Endocrinologia, Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brasil
| | - André F. Reis
- Universidade Federal de São PauloSão PauloSPBrasil Disciplina de Endocrinologia, Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brasil
| | - Fernando M. A. Giuffrida
- Universidade Federal de São PauloSão PauloSPBrasil Disciplina de Endocrinologia, Universidade Federal de São Paulo (Unifesp), São Paulo, SP, Brasil
- Departamento de Ciências da VidaUniversidade do Estado da BahiaSalvadorBABrasil Departamento de Ciências da Vida, Universidade do Estado da Bahia (Uneb), Salvador, BA, Brasil
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Wang T, Zhu M, Wang Y, Hu C, Fang C, Hu J. Two novel GCK mutations in Chinese patients with maturity-onset diabetes of the young. Endocrine 2024; 83:92-98. [PMID: 37847371 DOI: 10.1007/s12020-023-03509-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Accepted: 08/25/2023] [Indexed: 10/18/2023]
Abstract
PURPOSE Heterozygous inactivating mutations in the glucokinase (GCK) gene result in the asymptomatic fasting hyperglycemia named as GCK-MODY or MODY2. The genetic testing can effectively avoid the misdiagnosis and inappropriate treatment for GCK-MODY. METHODS A total of 25 unrelated families with MODY were screened for mutations in coding region of GCK by using direct sequencing. Three different bioinformatics tools such as PolyPhen2, Mutation Taster and PROVEAN were performed to predict the function of mutant proteins. The glucose profile was recorded by continuous glucose monitoring system (CGMS) to evaluate the glycemic variability for the GCK-MODY patient. RESULTS Our study identified five GCK mutations in 24% of the families (6/25): two novel mutations (I126fs and G385A) and three already described mutations (G44S, H50fs and S383L). In silico analyses predicted that these mutations altered structural conformational changes. The values of mean amplitude of glycemic excursions (MAGE), an important index of blood glucose fluctuation in CGMS system, were 0.81 in the first 24 h and 1.61 in the second 24 h record in the patient with GCK-MODY (F3), suggesting little glucose fluctuation. CONCLUSION The genetic testing is suggested to be important to differentiate GCK-MODY from other types of diabetes. CGMS might be used to screen GCK-MODY cases prior to genetic testing.
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Affiliation(s)
- Tao Wang
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China
| | - Mengmeng Zhu
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China
| | - Yun Wang
- Department of Clinical Laboratory, Suzhou Guangji Hospital, Suzhou, 215123, China
| | - Cheng Hu
- Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, 200233, China
| | - Chen Fang
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China.
| | - Ji Hu
- Department of Endocrinology, The Second Affiliated Hospital of Soochow University, Suzhou, 215004, China.
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Amaratunga SA, Hussein Tayeb T, Muhamad Sediq RN, Hama Salih FK, Dusatkova P, Wakeling MN, De Franco E, Pruhova S, Lebl J. Paediatric diabetes subtypes in a consanguineous population: a single-centre cohort study from Kurdistan, Iraq. Diabetologia 2024; 67:113-123. [PMID: 37897565 PMCID: PMC10709478 DOI: 10.1007/s00125-023-06030-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2023] [Accepted: 09/11/2023] [Indexed: 10/30/2023]
Abstract
AIMS/HYPOTHESIS Monogenic diabetes is estimated to account for 1-6% of paediatric diabetes cases in primarily non-consanguineous populations, while the incidence and genetic spectrum in consanguineous regions are insufficiently defined. In this single-centre study we aimed to evaluate diabetes subtypes, obtain the consanguinity rate and study the genetic background of individuals with syndromic and neonatal diabetes in a population with a high rate of consanguinity. METHODS Data collection was carried out cross-sectionally in November 2021 at the paediatric diabetic clinic, Dr Jamal Ahmad Rashed Hospital, in Sulaimani, Kurdistan, Iraq. At the time of data collection, 754 individuals with diabetes (381 boys) aged up to 16 years were registered. Relevant participant data was obtained from patient files. Consanguinity status was known in 735 (97.5%) participants. Furthermore, 12 families of children with neonatal diabetes and seven families of children with syndromic diabetes consented to genetic testing by next-generation sequencing. Prioritised variants were evaluated using the American College of Medical Genetics and Genomics guidelines and confirmed by Sanger sequencing. RESULTS A total of 269 of 735 participants (36.5%) with known consanguinity status were offspring of consanguineous families. An overwhelming majority of participants (714/754, 94.7%) had clinically defined type 1 diabetes (35% of them were born to consanguineous parents), whereas only eight (1.1%) had type 2 diabetes (38% consanguineous). Fourteen (1.9%) had neonatal diabetes (50% consanguineous), seven (0.9%) had syndromic diabetes (100% consanguineous) and 11 (1.5%) had clinically defined MODY (18% consanguineous). We found that consanguinity was significantly associated with syndromic diabetes (p=0.0023) but not with any other diabetes subtype. The genetic cause was elucidated in ten of 12 participants with neonatal diabetes who consented to genetic testing (homozygous variants in GLIS3 [sibling pair], PTF1A and ZNF808 and heterozygous variants in ABCC8 and INS) and four of seven participants with syndromic diabetes (homozygous variants in INSR, SLC29A3 and WFS1 [sibling pair]). In addition, a participant referred as syndromic diabetes was diagnosed with mucolipidosis gamma and probably has type 2 diabetes. CONCLUSIONS/INTERPRETATION This unique single-centre study confirms that, even in a highly consanguineous population, clinically defined type 1 diabetes is the prevailing paediatric diabetes subtype. Furthermore, a pathogenic cause of monogenic diabetes was identified in 83% of tested participants with neonatal diabetes and 57% of participants with syndromic diabetes, with most variants being homozygous. Causative genes in our consanguineous participants were markedly different from genes reported from non-consanguineous populations and also from those reported in other consanguineous populations. To correctly diagnose syndromic diabetes in consanguineous populations, it may be necessary to re-evaluate diagnostic criteria and include additional phenotypic features such as short stature and hepatosplenomegaly.
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Affiliation(s)
- Shenali A Amaratunga
- Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic.
| | - Tara Hussein Tayeb
- Diabetic Clinic, Dr Jamah Ahmad Rashed Hospital, Sulaimani, Kurdistan, Iraq
- Department of Paediatrics, College of Medicine, Sulaimani University, Sulaimani, Kurdistan, Iraq
| | - Rozhan N Muhamad Sediq
- Diabetic Clinic, Dr Jamah Ahmad Rashed Hospital, Sulaimani, Kurdistan, Iraq
- Department of Paediatrics, College of Medicine, Sulaimani University, Sulaimani, Kurdistan, Iraq
| | | | - Petra Dusatkova
- Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic
| | - Matthew N Wakeling
- Clinical and Biomedical Sciences, University of Exeter Faculty of Health and Life Sciences, Exeter, UK
| | - Elisa De Franco
- Clinical and Biomedical Sciences, University of Exeter Faculty of Health and Life Sciences, Exeter, UK
| | - Stepanka Pruhova
- Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic
| | - Jan Lebl
- Department of Paediatrics, 2nd Faculty of Medicine, Charles University in Prague and Motol University Hospital, Prague, Czech Republic
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Svalastoga P, Kaci A, Molnes J, Solheim MH, Johansson BB, Krogvold L, Skrivarhaug T, Valen E, Johansson S, Molven A, Sagen JV, Søfteland E, Bjørkhaug L, Tjora E, Aukrust I, Njølstad PR. Characterisation of HNF1A variants in paediatric diabetes in Norway using functional and clinical investigations to unmask phenotype and monogenic diabetes. Diabetologia 2023; 66:2226-2237. [PMID: 37798422 PMCID: PMC10627920 DOI: 10.1007/s00125-023-06012-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2023] [Accepted: 06/09/2023] [Indexed: 10/07/2023]
Abstract
AIMS/HYPOTHESIS Correctly diagnosing MODY is important, as individuals with this diagnosis can discontinue insulin injections; however, many people are misdiagnosed. We aimed to develop a robust approach for determining the pathogenicity of variants of uncertain significance in hepatocyte nuclear factor-1 alpha (HNF1A)-MODY and to obtain an accurate estimate of the prevalence of HNF1A-MODY in paediatric cases of diabetes. METHODS We extended our previous screening of the Norwegian Childhood Diabetes Registry by 830 additional samples and comprehensively genotyped HNF1A variants in autoantibody-negative participants using next-generation sequencing. Carriers of pathogenic variants were treated by local healthcare providers, and participants with novel likely pathogenic variants and variants of uncertain significance were enrolled in an investigator-initiated, non-randomised, open-label pilot study (ClinicalTrials.gov registration no. NCT04239586). To identify variants associated with HNF1A-MODY, we functionally characterised their pathogenicity and assessed the carriers' phenotype and treatment response to sulfonylurea. RESULTS In total, 615 autoantibody-negative participants among 4712 cases of paediatric diabetes underwent genetic sequencing, revealing 19 with HNF1A variants. We identified nine carriers with novel variants classified as variants of uncertain significance or likely to be pathogenic, while the remaining ten participants carried five pathogenic variants previously reported. Of the nine carriers with novel variants, six responded favourably to sulfonylurea. Functional investigations revealed their variants to be dysfunctional and demonstrated a correlation with the resulting phenotype, providing evidence for reclassifying these variants as pathogenic. CONCLUSIONS/INTERPRETATION Based on this robust classification, we estimate that the prevalence of HNF1A-MODY is 0.3% in paediatric diabetes. Clinical phenotyping is challenging and functional investigations provide a strong complementary line of evidence. We demonstrate here that combining clinical phenotyping with functional protein studies provides a powerful tool to obtain a precise diagnosis of HNF1A-MODY.
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Affiliation(s)
- Pernille Svalastoga
- Mohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Alba Kaci
- Mohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway
- Center for Laboratory Medicine, Østfold Hospital Trust, Grålum, Norway
| | - Janne Molnes
- Mohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway
| | - Marie H Solheim
- Mohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Bente B Johansson
- Mohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway
| | - Lars Krogvold
- Division of Childhood and Adolescent Medicine, Oslo University Hospital, Oslo, Norway
| | - Torild Skrivarhaug
- Division of Childhood and Adolescent Medicine, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Eivind Valen
- Computational Biology Unit, Department of Informatics, University of Bergen, Bergen, Norway
- Sars International Centre for Marine Molecular Biology, University of Bergen, Bergen, Norway
| | - Stefan Johansson
- Mohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway
| | - Anders Molven
- Mohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Pathology, Haukeland University Hospital, Bergen, Norway
- Department of Clinical Medicine, University of Bergen, Bergen, Norway
| | - Jørn V Sagen
- Mohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway
| | - Eirik Søfteland
- Department of Medical Biochemistry and Pharmacology, Haukeland University Hospital, Bergen, Norway
- Department of Medicine, Haukeland University Hospital, Bergen, Norway
| | - Lise Bjørkhaug
- Department of Safety, Chemistry, and Biomedical Laboratory Sciences, Western Norway University of Applied Sciences, Bergen, Norway
| | - Erling Tjora
- Mohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway
- Children and Youth Clinic, Haukeland University Hospital, Bergen, Norway
| | - Ingvild Aukrust
- Mohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Medical Genetics, Haukeland University Hospital, Bergen, Norway
| | - Pål R Njølstad
- Mohn Center for Diabetes Precision Medicine, Department of Clinical Science, University of Bergen, Bergen, Norway.
- Children and Youth Clinic, Haukeland University Hospital, Bergen, Norway.
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Toomata Z, Leask M, Krishnan M, Cadzow M, Dalbeth N, Stamp LK, de Zoysa J, Merriman T, Wilcox P, Dewes O, Murphy R. Genetic testing for misclassified monogenic diabetes in Māori and Pacific peoples in Aōtearoa New Zealand with early-onset type 2 diabetes. Front Endocrinol (Lausanne) 2023; 14:1174699. [PMID: 37234800 PMCID: PMC10206310 DOI: 10.3389/fendo.2023.1174699] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 04/20/2023] [Indexed: 05/28/2023] Open
Abstract
Aims Monogenic diabetes accounts for 1-2% of diabetes cases yet is often misdiagnosed as type 2 diabetes. The aim of this study was to examine in Māori and Pacific adults clinically diagnosed with type 2 diabetes within 40 years of age, (a) the prevalence of monogenic diabetes in this population (b) the prevalence of beta-cell autoantibodies and (c) the pre-test probability of monogenic diabetes. Methods Targeted sequencing data of 38 known monogenic diabetes genes was analyzed in 199 Māori and Pacific peoples with BMI of 37.9 ± 8.6 kg/m2 who had been diagnosed with type 2 diabetes between 3 and 40 years of age. A triple-screen combined autoantibody assay was used to test for GAD, IA-2, and ZnT8. MODY probability calculator score was generated in those with sufficient clinical information (55/199). Results No genetic variants curated as likely pathogenic or pathogenic were found. One individual (1/199) tested positive for GAD/IA-2/ZnT8 antibodies. The pre-test probability of monogenic diabetes was calculated in 55 individuals with 17/55 (31%) scoring above the 20% threshold considered for diagnostic testing referral. Discussion Our findings suggest that monogenic diabetes is rare in Māori and Pacific people with clinical age, and the MODY probability calculator likely overestimates the likelihood of a monogenic cause for diabetes in this population.
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Affiliation(s)
- Zanetta Toomata
- Department of Medicine, Waipapa Taumata Rau, The University of Auckland, Auckland, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand
| | - Megan Leask
- Department of Biochemistry, University of Otago, Dunedin, New Zealand
- Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Mohanraj Krishnan
- Department of Biostatistics, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pittsburgh, PA, United States
| | - Murray Cadzow
- Department of Biochemistry, University of Otago, Dunedin, New Zealand
| | - Nicola Dalbeth
- Department of Medicine, Waipapa Taumata Rau, The University of Auckland, Auckland, New Zealand
| | - Lisa K. Stamp
- Department of Medicine, University of Otago, Christchurch, Christchurch, New Zealand
| | - Janak de Zoysa
- Department of Medicine, Waipapa Taumata Rau, The University of Auckland, Auckland, New Zealand
| | - Tony Merriman
- Department of Biochemistry, University of Otago, Dunedin, New Zealand
- Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Phillip Wilcox
- Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand
- Department of Mathematics and Statistics, University of Otago, Dunedin, New Zealand
| | - Ofa Dewes
- Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand
- Langimalie Research Centre, Auckland, New Zealand
- Centre of Methods and Policy Application in the Social Sciences, The University of Auckland, Auckland, New Zealand
| | - Rinki Murphy
- Department of Medicine, Waipapa Taumata Rau, The University of Auckland, Auckland, New Zealand
- Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand
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Prescriptions for insulin and insulin analogues in children with and without major congenital anomalies: a data linkage cohort study across six European regions. Eur J Pediatr 2023; 182:2235-2244. [PMID: 36869270 PMCID: PMC10175355 DOI: 10.1007/s00431-023-04885-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 02/15/2023] [Accepted: 02/16/2023] [Indexed: 03/05/2023]
Abstract
Are children with major congenital anomalies more likely to develop diabetes requiring insulin therapy, as indicated by prescriptions for insulin, than children without congenital anomalies? The aim of this study is to evaluate prescription rates of insulin/insulin analogues in children aged 0-9 years with and without major congenital anomalies. A EUROlinkCAT data linkage cohort study, involving six population-based congenital anomaly registries in five countries. Data on children with major congenital anomalies (60,662) and children without congenital anomalies (1,722,912), the reference group, were linked to prescription records. Birth cohort and gestational age were examined. The mean follow-up for all children was 6.2 years. In children with congenital anomalies aged 0-3 years, 0.04 per 100 child-years (95% CIs 0.01-0.07) had > 1 prescription for insulin/insulin analogues compared with 0.03 (95% CIs 0.01-0.06) in reference children, increasing ten-fold by age 8-9 years. The risk of > 1 prescription for insulin/insulin analogues aged 0-9 years in children with non-chromosomal anomalies (RR 0.92, 95% CI 0.84-1.00) was similar to that of reference children. However, children with chromosomal anomalies (RR 2.37, 95% CI 1.91-2.96), and specifically children with Down syndrome (RR 3.44, 95% CIs 2.70-4.37), Down syndrome with congenital heart defects (RR 3.86, 95% CIs 2.88-5.16) and Down syndrome without congenital heart defects (RR 2.78, 95% CIs 1.82-4.27), had a significantly increased risk of > 1 prescription for insulin/insulin analogues aged 0-9 years compared to reference children. Female children had a reduced risk of > 1 prescription aged 0-9 years compared with male children (RR 0.76, 95% CI 0.64-0.90 for children with congenital anomalies and RR 0.90, 95% CI 0.87-0.93 for reference children). Children without congenital anomalies born preterm (< 37 weeks) were more likely to have > 1 insulin/insulin analogue prescription compared to term births (RR 1.28, 95% CIs 1.20-1.36). CONCLUSION This is the first population-based study using a standardised methodology across multiple countries. Males, children without congenital anomalies born preterm and those with chromosomal anomalies had an increased risk of being prescribed insulin/insulin analogues. These results will help clinicians to identify which congenital anomalies are associated with an increased risk of developing diabetes requiring insulin therapy and allow them to reassure families of children who have non-chromosomal anomalies that their risk is similar to that of the general population. WHAT IS KNOWN • Children and young adults with Down syndrome have an increased risk of diabetes requiring insulin therapy. • Children born prematurely have an increased risk of developing diabetes requiring insulin therapy. WHAT IS NEW • Children with non-chromosomal anomalies do not have an increased risk of developing diabetes requiring insulin therapy compared to children without congenital anomalies. • Female children, with or without major congenital anomalies, are less likely to develop diabetes requiring insulin therapy before the age of 10 compared to male children.
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Harsunen M, Kettunen JLT, Härkönen T, Dwivedi O, Lehtovirta M, Vähäsalo P, Veijola R, Ilonen J, Miettinen PJ, Knip M, Tuomi T. Identification of monogenic variants in more than ten per cent of children without type 1 diabetes-related autoantibodies at diagnosis in the Finnish Pediatric Diabetes Register. Diabetologia 2023; 66:438-449. [PMID: 36418577 PMCID: PMC9892083 DOI: 10.1007/s00125-022-05834-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2022] [Accepted: 10/05/2022] [Indexed: 11/25/2022]
Abstract
AIMS/HYPOTHESIS Monogenic forms of diabetes (MODY, neonatal diabetes mellitus and syndromic forms) are rare, and affected individuals may be misclassified and treated suboptimally. The prevalence of type 1 diabetes is high in Finnish children but systematic screening for monogenic diabetes has not been conducted. We assessed the prevalence and clinical manifestations of monogenic diabetes in children initially registered with type 1 diabetes in the Finnish Pediatric Diabetes Register (FPDR) but who had no type 1 diabetes-related autoantibodies (AABs) or had only low-titre islet cell autoantibodies (ICAs) at diagnosis. METHODS The FPDR, covering approximately 90% of newly diagnosed diabetic individuals aged ≤15 years in Finland starting from 2002, includes data on diabetes-associated HLA genotypes and AAB data (ICA, and autoantibodies against insulin, GAD, islet antigen 2 and zinc transporter 8) at diagnosis. A next generation sequencing gene panel including 42 genes was used to identify monogenic diabetes. We interpreted the variants in HNF1A by using the gene-specific standardised criteria and reported pathogenic and likely pathogenic findings only. For other genes, we also reported variants of unknown significance if an individual's phenotype suggested monogenic diabetes. RESULTS Out of 6482 participants, we sequenced DNA for 152 (2.3%) testing negative for all AABs and 49 (0.8%) positive only for low-titre ICAs (ICAlow). A monogenic form of diabetes was revealed in 19 (12.5%) of the AAB-negative patients (14 [9.2%] had pathogenic or likely pathogenic variants) and two (4.1%) of the ICAlow group. None had ketoacidosis at diagnosis or carried HLA genotypes conferring high risk for type 1 diabetes. The affected genes were GCK, HNF1A, HNF4A, HNF1B, INS, KCNJ11, RFX6, LMNA and WFS1. A switch from insulin to oral medication was successful in four of five patients with variants in HNF1A, HNF4A or KCNJ11. CONCLUSIONS/INTERPRETATION More than 10% of AAB-negative children with newly diagnosed diabetes had a genetic finding associated with monogenic diabetes. Because the genetic diagnosis can lead to major changes in treatment, we recommend referring all AAB-negative paediatric patients with diabetes for genetic testing. Low-titre ICAs in the absence of other AABs does not always indicate a diagnosis of type 1 diabetes.
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Affiliation(s)
- Minna Harsunen
- New Children's Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
- Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland.
- Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland.
| | - Jarno L T Kettunen
- Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland.
- Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland.
- Abdominal Centre, Endocrinology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
- Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland.
| | - Taina Härkönen
- Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland
| | - Om Dwivedi
- Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland
- Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland
| | - Mikko Lehtovirta
- Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland
| | - Paula Vähäsalo
- Department of Pediatrics, PEDEGO Research Unit, University of Oulu, Oulu, Finland
- Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland
- Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Riitta Veijola
- Department of Pediatrics, PEDEGO Research Unit, University of Oulu, Oulu, Finland
- Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland
- Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland
| | - Jorma Ilonen
- Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland
| | - Päivi J Miettinen
- New Children's Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Translational Stem Cell Biology and Metabolism Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Mikael Knip
- New Children's Hospital, Pediatric Research Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland
- Tampere Center for Child Health Research, Tampere University Hospital, Tampere, Finland
| | - Tiinamaija Tuomi
- Folkhälsan Research Center, Biomedicum Helsinki, Helsinki, Finland
- Research Program for Clinical and Molecular Metabolism, University of Helsinki, Helsinki, Finland
- Abdominal Centre, Endocrinology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
- Finnish Institute for Molecular Medicine, University of Helsinki, Helsinki, Finland
- Lund University Diabetes Centre, Department of Clinical Sciences, Lund University, Lund, Sweden
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Guan G, Qin T, Zhao LL, Jin P. Genetic and Functional Analyses of the Novel KLF11 Pro193Thr Variant in a Three-Generation Family with MODY7. Horm Metab Res 2023; 55:136-141. [PMID: 36241199 DOI: 10.1055/a-1961-6281] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
KLF11 regulates insulin gene expression through binding to the insulin promoter and has been reported as a causative gene for maturity-onset diabetes of the young 7 (MODY7). Here, we report a novel KLF11 variant associated with a three-generation family with early childhood-onset diabetes and explore its clinical and functional characteristics. The three-generational pedigree contains five patients affected by diabetes. The pathogenic variant identified by whole-exome sequencing was further confirmed by Sanger sequencing and pedigree verification. Luciferase reporter assays and glucose-stimulated insulin secretion were used to examine whether the KLF11 variant binds to the insulin promoter and regulate insulin secretion in vitro. The proband, his son, and his uncle exhibited hyperglycemia at ages 32, 13 and 71 years, respectively. All three patients showed characteristics of metabolic syndrome (obesity, dyslipidemia, and diabetes), but the insulin secretion of islet β-cells was impaired. A novel heterozygous missense variant, c.577 C>A (p.Pro193Thr) of the KLF11 gene was detected in all three patients. This variant co-segregates with the diabetes phenotype, consistent with an autosomal dominant disorder. The identified KLF11 p.Pro193Thr variant drastically decreased the transcriptional activity of KLF11, as demonstrated by luciferase reporter assay. Functional analyses revealed that the KLF11 Pro193Thr variant inhibited glucose-stimulated insulin secretion. We identified a novel KLF11 Pro193Thr variant in a three generation family with MODY7. These findings shed light on the molecular mechanisms underlying the pathogenesis of MODY7 and expand the genotype and clinical spectrum of MODY7.
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Affiliation(s)
- Gaopeng Guan
- Department of Endocrinology, Central South University Third Xiangya Hospital, Changsha, China
| | - Tiantian Qin
- Department of Endocrinology, Central South University Third Xiangya Hospital, Changsha, China
| | - Li-Ling Zhao
- Department of Endocrinology, Central South University Third Xiangya Hospital, Changsha, China
| | - Ping Jin
- Department of Endocrinology, Central South University Third Xiangya Hospital, Changsha, China
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Libman I, Haynes A, Lyons S, Pradeep P, Rwagasor E, Tung JYL, Jefferies CA, Oram RA, Dabelea D, Craig ME. ISPAD Clinical Practice Consensus Guidelines 2022: Definition, epidemiology, and classification of diabetes in children and adolescents. Pediatr Diabetes 2022; 23:1160-1174. [PMID: 36537527 DOI: 10.1111/pedi.13454] [Citation(s) in RCA: 98] [Impact Index Per Article: 32.7] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/09/2022] [Indexed: 12/24/2022] Open
Affiliation(s)
- Ingrid Libman
- Division of Pediatric Endocrinology, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Aveni Haynes
- Children's Diabetes Centre, Telethon Kids Institute, Perth, Western Australia, Australia
| | - Sarah Lyons
- Pediatric Diabetes and Endocrinology, Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA
| | - Praveen Pradeep
- Department of Endocrinology, All India Institute of Medical Sciences, New Delhi, India
| | - Edson Rwagasor
- Rwanda Biomedical Center, Rwanda Ministry of Health, Kigali, Rwanda
| | - Joanna Yuet-Ling Tung
- Department of Paediatrics and Adolescent Medicine, Hong Kong Children's Hospital, Hong Kong, Hong Kong
| | - Craig A Jefferies
- Starship Children's Health, Te Whatu Ora Health New Zealand, Auckland, New Zealand
| | - Richard A Oram
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, Exeter, UK
| | - Dana Dabelea
- Department of Epidemiology, University of Colorado School of Medicine, Aurora, Colorado, USA
| | - Maria E Craig
- The Children's Hospital at Westmead, Sydney, New South Wales (NSW), Australia.,University of Sydney Children's Hospital Westmead Clinical School, Sydney, NEW, Australia.,Discipline of Paediatrics & Child Health, School of Clinical Medicine, University of NSW Medicine & Health, Sydney, NSW, Australia
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15
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Limbert C, Lanzinger S, deBeaufort C, Iotova V, Pelicand J, Prieto M, Schiaffini R, Šumnik Z, Pacaud D. Diabetes-related antibody-testing is a valuable screening tool for identifying monogenic diabetes - A survey from the worldwide SWEET registry. Diabetes Res Clin Pract 2022; 192:110110. [PMID: 36183869 DOI: 10.1016/j.diabres.2022.110110] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 09/19/2022] [Accepted: 09/25/2022] [Indexed: 11/26/2022]
Abstract
AIMS To evaluate access to screening tools for monogenic diabetes in paediatric diabetes centres across the world and its impact on diagnosis and clinical outcomes of children and youth with genetic forms of diabetes. METHODS 79 centres from the SWEET diabetes registry including 53,207 children with diabetes participated in a survey on accessibility and use of diabetes related antibodies, c-peptide and genetic testing. RESULTS 73, 63 and 62 participating centres had access to c-peptide, antibody and genetic testing, respectively. Access to antibody testing was associated with higher proportion of patients with rare forms of diabetes identified with monogenic diabetes (54 % versus 17 %, p = 0.01), lower average whole clinic HbA1c (7.7[Q1,Q2: 7.3-8.0]%/61[56-64]mmol/mol versus 9.2[8.6-10.0]%/77[70-86]mmol/mol, p < 0.001) and younger age at onset (8.3 [7.3-8.8] versus 9.7 [8.6-12.7] years p < 0.001). Additional access to c-peptide or genetic testing was not related to differences in age at onset or HbA1c outcome. CONCLUSIONS Clinical suspicion and antibody testing are related to identification of different types of diabetes. Implementing access to comprehensive antibody screening may provide important information for selecting individuals for further genetic evaluation. In addition, worse overall clinical outcomes in centers with limited diagnostic capabilities indicate they may also need support for individualized diabetes management. TRIAL REGISTRATION NCT04427189.
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Affiliation(s)
- Catarina Limbert
- Hospital Dona Estefânia, Unit of Paediatric Endocrinology and Diabetes, Lisbon, Portugal; Nova Medical School, Universidade Nova de Lisboa, Lisbon, Portugal.
| | - Stefanie Lanzinger
- Institute of Epidemiology and Medical Biometry, ZIBMT, University of Ulm, Ulm, Germany; German Centre for Diabetes Research (DZD), München-Neuherberg, Germany
| | - Carine deBeaufort
- Department of Paediatric Diabetes and Endocrinology, Centre Hospitalier Luxembourg, Luxembourg, Luxembourg
| | - Violeta Iotova
- Department of Paediatrics, Medical University of Varna, Varna, Bulgaria
| | - Julie Pelicand
- San Camilo Hospital-Medicine School, Universidad de Valparaíso, San Felipe, Chile
| | - Mariana Prieto
- Servicio de Nutrición, Hospital de Pediatría SAMIC J. P. Garrahan, 1245 Buenos Aieres, Argentina
| | | | - Zdeněk Šumnik
- Department of Paediatrics, Second Faculty of Medicine, Charles University and Motol University Hospital, Prague, Czech Republic
| | - Danièle Pacaud
- Alberta Children's Hospital Research Institute, University of Calgary, Calgary, AB, Canada; Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
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16
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Tosur M, Philipson LH. Precision diabetes: Lessons learned from maturity-onset diabetes of the young (MODY). J Diabetes Investig 2022; 13:1465-1471. [PMID: 35638342 PMCID: PMC9434589 DOI: 10.1111/jdi.13860] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 05/20/2022] [Accepted: 05/27/2022] [Indexed: 11/28/2022] Open
Abstract
Maturity-onset of diabetes of the young (MODY) are monogenic forms of diabetes characterized by early onset diabetes with autosomal dominant inheritance. Since its first description about six decades ago, there have been significant advancements in our understanding of MODY from clinical presentations to molecular diagnostics and therapeutic responses. The prevalence of MODY is estimated as at least 1.1-6.5% of the pediatric diabetes population with a high degree of geographic variability that might arise from several factors in the criteria used to ascertain cases. GCK-MODY, HNF1A-MODY, and HNF4A-MODY account for >90% of MODY cases. While some MODY forms do not require treatment (i.e., GCK-MODY), some others are highly responsive to oral agents (i.e., HNF1A-MODY). The risk of micro- and macro-vascular complications of diabetes also differ significantly between MODY forms. Despite its high clinical impact, 50-90% of MODY cases are estimated to be misdiagnosed as type 1 or type 2 diabetes. Although there are many clinical features suggestive of MODY diagnosis, there is no single clinical criterion. An online MODY Risk Calculator can be a useful tool for clinicians in the decision-making process for MODY genetic testing in some situations. Molecular genetic tests with a commercial gene panel should be performed in cases with a suspicion of MODY. Unresolved atypical cases can be further studied by exome or genome sequencing in a clinical or research setting, as available.
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Affiliation(s)
- Mustafa Tosur
- The Division of Diabetes and Endocrinology, Department of Pediatrics, Baylor College of MedicineTexas Children's HospitalHoustonTexasUSA
| | - Louis H Philipson
- Departments of Medicine and Pediatrics, Kovler Diabetes CenterUniversity of ChicagoChicagoIllinoisUSA
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17
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Holder M, Kapellen T, Ziegler R, Bürger-Büsing J, Danne T, Dost A, Holl RW, Holterhus PM, Karges B, Kordonouri O, Lange K, Müller S, Raile K, Schweizer R, von Sengbusch S, Stachow R, Wagner V, Wiegand S, Neu A. Diagnosis, Therapy and Follow-Up of Diabetes Mellitus in Children and Adolescents. Exp Clin Endocrinol Diabetes 2022; 130:S49-S79. [PMID: 35913059 DOI: 10.1055/a-1624-3388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Affiliation(s)
- Martin Holder
- Klinikum Stuttgart, Olgahospital, Department of Pediatric Endocrinology and Diabetology, Germany
| | - Thomas Kapellen
- Department of Paediatrics and Adolescent Medicine, University Hospital, Leipzig, Germany
| | - Ralph Ziegler
- Practice for Paediatrics and Adolescent Medicine, Focus on Diabetology, Münster, Germany
| | - Jutta Bürger-Büsing
- Association of Diabetic Children and Adolescents, Diabetes Center, Kaiserslautern, Germany
| | - Thomas Danne
- Children's and Youth Hospital Auf der Bult, Hannover, Germany
| | - Axel Dost
- Department of Paediatrics and Adolescent Medicine, University Hospital Jena, Germany
| | - Reinhard W Holl
- Institute for Epidemiology and Medical Biometry, ZIBMT, University of Ulm, Germany
| | - Paul-Martin Holterhus
- Department of General Paediatrics, University Hospital Schleswig-Holstein, Kiel Campus, Germany
| | - Beate Karges
- Endocrinology and Diabetology Section, University Hospital, RWTH Aachen University, Germany
| | - Olga Kordonouri
- Children's and Youth Hospital Auf der Bult, Hannover, Germany
| | - Karin Lange
- Department of Medical Psychology, Hannover Medical School, Hannover, Germany
| | | | - Klemens Raile
- Virchow Hospital, University Medicine, Berlin, Germany
| | - Roland Schweizer
- Department of Pediatrics and Adolescent Medicine, University Hospital Tübingen, Germany
| | - Simone von Sengbusch
- Department of Paediatrics and Adolescent Medicine, University Hospital Schleswig-Holstein, Campus Lübeck, Germany
| | - Rainer Stachow
- Sylt Specialist Hospital for Children and Adolescents, Westerland, Germany
| | - Verena Wagner
- Joint Practice for Paediatrics and Adolescent Medicine, Rostock, Germany
| | | | - Andreas Neu
- Department of Pediatrics and Adolescent Medicine, University Hospital Tübingen, Germany
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18
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Saeed M, Stene LC, Ariansen I, Tell GS, Tapia G, Joner G, Skrivarhaug T. Nine-fold higher risk of acute myocardial infarction in subjects with type 1 diabetes compared to controls in Norway 1973-2017. Cardiovasc Diabetol 2022; 21:59. [PMID: 35477506 PMCID: PMC9047315 DOI: 10.1186/s12933-022-01498-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 04/09/2022] [Indexed: 02/27/2023] Open
Abstract
BACKGROUND We aimed to study the cumulative incidence and risk factors (sex, age, calendar year of diabetes onset, country of origin and educational level) of acute myocardial infarction (AMI) in subjects with type 1 diabetes and matched controls. METHODS A nationwide cohort of subjects with type 1 diabetes diagnosed at age < 15 years in Norway during 1973-2000 was followed until the first AMI event, emigration, death or 31st of December 2017. The Norwegian Childhood Diabetes Registry was linked to five nationwide registries, and up to ten sex- and age-matched controls per case were included. RESULTS Among 7086 subjects with type 1 diabetes, 170 (2.4%) were identified with incident AMI, compared to 193 (0.3%) of 69,356 controls. Mean age and diabetes duration at first AMI was 40.8 years and 30.6 years, respectively. The probability of AMI after 40 years of follow-up was 8.0% in subjects with type 1 diabetes and 1.1% in controls, aHR 9.05 (95% CI 7.18-11.41). In type 1 diabetes, male sex (aHR 1.45), higher age at onset of diabetes and lower education (higher compared to lower, aHR 0.38) were significantly associated with higher risk of AMI. There was no significant time trend in AMI by calendar year of diabetes onset. CONCLUSIONS We found nine-fold excess risk of AMI in subjects with type 1 diabetes, and three-fold higher risk in subjects with low versus high education. These results highlight a strengthened focus on prevention of cardiovascular disease, and diabetes education tailored to the subjects' educational background.
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Affiliation(s)
- Maryam Saeed
- Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway. .,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. .,Oslo Diabetes Research Centre, Oslo University Hospital, Oslo, Norway.
| | - Lars C Stene
- Oslo Diabetes Research Centre, Oslo University Hospital, Oslo, Norway.,Department of Chronic Diseases, Norwegian Institute of Public Health, Oslo, Norway
| | - Inger Ariansen
- Department of Chronic Diseases, Norwegian Institute of Public Health, Oslo, Norway
| | - Grethe S Tell
- Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway
| | - German Tapia
- Department of Chronic Diseases, Norwegian Institute of Public Health, Oslo, Norway
| | - Geir Joner
- Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway
| | - Torild Skrivarhaug
- Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.,Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.,Oslo Diabetes Research Centre, Oslo University Hospital, Oslo, Norway
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19
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Wu H, Patterson CC, Zhang X, Ghani RBA, Magliano DJ, Boyko EJ, Ogle GD, Luk AOY. Worldwide estimates of incidence of type 2 diabetes in children and adolescents in 2021. Diabetes Res Clin Pract 2022; 185:109785. [PMID: 35189261 DOI: 10.1016/j.diabres.2022.109785] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 01/21/2022] [Accepted: 02/14/2022] [Indexed: 12/19/2022]
Abstract
AIMS We aimed to conduct a systematic review of published studies on the incidence of type 2 diabetes in children and adolescents aged under 20 years and provide worldwide incidence estimates for 2021. METHODS We used MEDLINE and EMBASE to identify studies reporting type 2 diabetes incidence in children and adolescents published between Jan 2000 and April 2021. We used a negative binomial regression model to develop a prediction equation to estimate incidence rates from country characteristics. We applied the resulting incidence predictions to country population data to estimate numbers of incident cases in children and adolescents by International Diabetes Federation (IDF) region and World Bank income classification group. RESULTS We estimate that there are approximately 41,600 new cases of diagnosed type 2 diabetes among children and adolescents in 2021 worldwide. Around 30% and 40% of the worldwide total incident cases are in IDF Western Pacific region and in World Bank upper-middle-income countries, respectively. The three countries with the highest estimated number of incident cases are China, India, and United States of America. CONCLUSIONS The number of newly diagnosed type 2 diabetes in children and adolescents is substantial. More reliable data are needed to track the incidence of type 2 diabetes in children and adolescents.
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Affiliation(s)
- Hongjiang Wu
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China
| | | | - Xinge Zhang
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China
| | - Ruhina Binta A Ghani
- Centre for Public Health, Queen's University Belfast, United Kingdom; Health, Nutrition and Population Programme, BRAC, Bangladesh
| | | | - Edward J Boyko
- Seattle Epidemiologic Research and Information Center, VA Puget Sound, and Department of Medicine, University of Washington, Seattle, WA, USA
| | - Graham D Ogle
- Life for a Child Program, Diabetes NSW & ACT, 26 Arundel St., Glebe NSW 2037, Australia
| | - Andrea O Y Luk
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China; Hong Kong Institute of Diabetes and Obesity, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China; Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, People's Republic of China.
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20
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Xu Q, Kan CX, Hou NN, Sun XD. Novel HNF1A gene mutation in maturity-onset diabetes of the young: A case report. World J Clin Cases 2022; 10:1909-1913. [PMID: 35317157 PMCID: PMC8891774 DOI: 10.12998/wjcc.v10.i6.1909] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 10/26/2021] [Accepted: 01/14/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Maturity-onset diabetes of the young 3 (MODY3), caused by mutations in the HNF1A gene, is the most common subtype of MODY. The diagnosis of MODY3 is critical because a low dose of sulfonylurea agents can achieve glucose control. CASE SUMMARY We describe a patient with MODY3 involving a novel splicing mutation, in whom low-dose gliclazide was sufficient to control clinically significant hyperglycemia. Sanger sequencing identified a splicing HNF1A mutation in 12q24 NM_000545.5 Intron5 c.1108-1G>A. Glycemic control has been maintained without insulin therapy for 28 mo after the diagnosis of diabetes. CONCLUSION This case report highlights a novel HNF1A gene mutation in MODY3 that is responsive to sulfonylurea therapy.
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Affiliation(s)
- Qian Xu
- Department of Endocrinology and Metabolism, Clinical Research Center, The Affiliated Hospital of Weifang Medical University, Weifang 261031, Shandong Province, China
| | - Cheng-Xia Kan
- Department of Endocrinology and Metabolism, Clinical Research Center, The Affiliated Hospital of Weifang Medical University, Weifang 261031, Shandong Province, China
| | - Ning-Ning Hou
- Department of Endocrinology and Metabolism, Clinical Research Center, The Affiliated Hospital of Weifang Medical University, Weifang 261031, Shandong Province, China
| | - Xiao-Dong Sun
- Department of Endocrinology and Metabolism, Clinical Research Center, The Affiliated Hospital of Weifang Medical University, Weifang 261031, Shandong Province, China
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21
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Zmysłowska A, Jakiel P, Gadzalska K, Majos A, Płoszaj T, Ben-Skowronek I, Deja G, Glowinska-Olszewska B, Jarosz-Chobot P, Klonowska B, Kowalska I, Mlynarski W, Mysliwiec M, Nazim J, Noczynska A, Robak-Kontna K, Skala-Zamorowska E, Skowronska B, Szadkowska A, Szypowska A, Walczak M, Borowiec M. Next- generation sequencing is an effective method for diagnosing patients with different forms of monogenic diabetes. Diabetes Res Clin Pract 2022; 183:109154. [PMID: 34826540 DOI: 10.1016/j.diabres.2021.109154] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Revised: 11/13/2021] [Accepted: 11/20/2021] [Indexed: 11/03/2022]
Abstract
AIM Monogenic diabetes (MD) represents 5-7% of antibody-negative diabetes cases and is a heterogeneous group of disorders. METHODS We used targeted next-generation sequencing (NGS) on Illumina NextSeq 550 platform involving the SureSelect assay to perform genetic and clinical characteristics of a study group of 684 individuals, including 542 patients referred from 12 Polish Diabetes Centers with suspected MD diagnosed between December 2016 and December 2019 and their 142 family members (FM). RESULTS In 198 probands (36.5%) and 66 FM (46.5%) heterozygous causative variants were confirmed in 11 different MD-related genes, including 31 novel mutations, with the highest number in the GCK gene (206/264), 22/264 in the HNF1A gene and 8/264 in the KCNJ11 gene. Of the 183 probands with MODY1-5 diabetes, 48.6% of them were diagnosed at the pre-diabetes stage and most of them (68.7%) were on diet only at the time of genetic diagnosis, while 31.3% were additionally treated with oral hypoglycaemic drugs and/or insulin. CONCLUSIONS In summary, the results obtained confirm the efficacy of targeted NGS method in the molecular diagnosis of patients with suspected MD and broaden the spectrum of new causal variants, while updating our knowledge of the clinical features of patients defined as having MD.
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Affiliation(s)
- A Zmysłowska
- Department of Clinical Genetics, Medical University of Lodz, Lodz, Poland.
| | - P Jakiel
- Department of Clinical Genetics, Medical University of Lodz, Lodz, Poland
| | - K Gadzalska
- Department of Clinical Genetics, Medical University of Lodz, Lodz, Poland
| | - A Majos
- Department of General and Transplant Surgery, Medical University of Lodz, Lodz, Poland
| | - T Płoszaj
- Department of Clinical Genetics, Medical University of Lodz, Lodz, Poland
| | - I Ben-Skowronek
- Department of Pediatric Endocrinology and Diabetology, Medical University of Lublin, Lublin, Poland
| | - G Deja
- Department of Children's Diabetology, Medical University of Silesia in Katowice, Poland
| | - B Glowinska-Olszewska
- Department of Pediatrics, Endocrinology, Diabetology with Cardiology Division, Medical University of Bialystok, Bialystok, Poland
| | - P Jarosz-Chobot
- Department of Children's Diabetology, Medical University of Silesia in Katowice, Poland
| | - B Klonowska
- Department of Clinical Pediatrics, University of Warmia and Mazury in Olsztyn, Provincial Specialist Children's Hospital, Olsztyn, Poland
| | - I Kowalska
- Department of Internal Medicine and Metabolic Diseases, Medical University of Bialystok, Bialystok, Poland
| | - W Mlynarski
- Department of Pediatrics, Oncology and Hematology, Medical University of Lodz, Lodz, Poland
| | - M Mysliwiec
- Department of Pediatrics, Diabetology and Endocrinology, Medical University of Gdansk, Gdansk, Poland
| | - J Nazim
- Department of Pediatric Endocrinology, Jagiellonian University Medical College, Cracow, Poland
| | - A Noczynska
- Department of Pediatric Endocrinology and Diabetology, Wroclaw Medical University, Wroclaw, Poland
| | - K Robak-Kontna
- Outpatient Clinic for Pediatric Diabetology, Regional Children's Hospital in Bydgoszcz, Bydgoszcz, Poland
| | - E Skala-Zamorowska
- Department of Children's Diabetology, Medical University of Silesia in Katowice, Poland
| | - B Skowronska
- Department of Pediatric Diabetes and Obesity, Poznan University of Medical Sciences, Poznan, Poland
| | - A Szadkowska
- Department of Pediatrics, Diabetology, Endocrinology and Nephrology, Medical University of Lodz, Lodz, Poland
| | - A Szypowska
- Department of Pediatrics, Medical University of Warsaw, Warsaw, Poland
| | - M Walczak
- Department of Pediatrics, Endocrinology, Diabetology, Metabolic Diseases and Cardiology of the Developmental Age, Pomeranian Medical University in Szczecin, Szczecin, Poland
| | - M Borowiec
- Department of Clinical Genetics, Medical University of Lodz, Lodz, Poland
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22
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Lezzi M, Aloi C, Salina A, Fragola M, Bassi M, Strati MF, d’Annunzio G, Minuto N, Maghnie M. Diabetes Mellitus Diagnosed in Childhood and Adolescence With Negative Autoimmunity: Results of Genetic Investigation. Front Endocrinol (Lausanne) 2022; 13:894878. [PMID: 35769090 PMCID: PMC9235348 DOI: 10.3389/fendo.2022.894878] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Accepted: 05/03/2022] [Indexed: 11/22/2022] Open
Abstract
Monogenic diabetes is a rare form of diabetes, accounting for approximately 1% to 6% of pediatric diabetes patients. Some types of monogenic diabetes can be misdiagnosed as type 1 diabetes in children or adolescents because of similar clinical features. Identification of the correct etiology of diabetes is crucial for clinical, therapeutic, and prognostic issues. Our main objective was to determine the prevalence of monogenic diabetes in patients with diabetes mellitus, diagnosed in childhood or in adolescence, and negative autoimmunity. We retrospectively analyzed clinical data of 275 patients diagnosed with insulin-dependent diabetes at age <18yr in the last 10 years. 8.4% of subjects has negative autoimmunity. Their DNA was sequenced by NGS custom panel composed by 45 candidate genes involved in glucose metabolism disorder. Two novel heterozygous pathogenic or likely pathogenic variants (10,5% of autoantibody negative subjects) were detected: the frameshift variant c.617_618insA in NEUROD1 exon 2 and the missense change c.116T>C in INS exon 2. Our study corroborates previous results of other reports in literature. NGS assays are useful methods for a correct diagnosis of monogenic diabetes, even of rarest forms, highlighting mechanisms of pediatric diabetes pathogenesis.
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Affiliation(s)
- Marilea Lezzi
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
- Department of Pediatrics, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Concetta Aloi
- LABSIEM (Laboratory for the Study of Inborn Errors of Metabolism), IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Alessandro Salina
- LABSIEM (Laboratory for the Study of Inborn Errors of Metabolism), IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Martina Fragola
- Department of Hematology and Oncology, Epidemiology and Biostatistics Section, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Marta Bassi
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
- Department of Pediatrics, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | - Marina Francesca Strati
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
- Department of Pediatrics, IRCCS Istituto Giannina Gaslini, Genoa, Italy
| | | | - Nicola Minuto
- Department of Pediatrics, IRCCS Istituto Giannina Gaslini, Genoa, Italy
- *Correspondence: Nicola Minuto,
| | - Mohamad Maghnie
- Department of Neuroscience, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Genoa, Italy
- Department of Pediatrics, IRCCS Istituto Giannina Gaslini, Genoa, Italy
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23
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Bratke H, Biringer E, Margeirsdottir HD, Njølstad PR, Skrivarhaug T. Relation of Health-Related Quality of Life with Glycemic Control and Use of Diabetes Technology in Children and Adolescents with Type 1 Diabetes: Results from a National Population Based Study. J Diabetes Res 2022; 2022:8401328. [PMID: 36387938 PMCID: PMC9649325 DOI: 10.1155/2022/8401328] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 10/05/2022] [Indexed: 11/06/2022] Open
Abstract
OBJECTIVE The primary aim was to analyse the association between diabetes-specific health-related quality of life (HRQOL) and HbA1c in children and adolescents with type 1 diabetes. The secondary aims were to evaluate the associations between diabetes-specific HRQOL and age, sex, diabetes duration, and the use of diabetes technology in diabetes treatment. Research Design and Methods. Children with type 1 diabetes (10-17 years, N = 1,019) and parents (children <10 years, N = 371; 10-17 years, N = 1,070) completed the DISABKIDS diabetes-specific questionnaire (DDM-10) as part of the 2017 data collection for the Norwegian Childhood Diabetes Registry. The DDM-10 consists of two subscales-'impact' and 'treatment'-with six and four items, respectively. In the linear regression models, the items and subscales were outcome variables, while HbA1c, age, sex, diabetes duration, insulin pump use, and continuous glucose monitoring (CGM) system use were predictor variables. RESULTS Lower HbA1c measurements and male sex were associated with higher HRQOL scores on both DDM-10 scales in the age group 10-17 years, but not in children under 10 years. Parents gave lower HRQOL scores than children in the 10-17 age group. Insulin pump and CGM use were not significantly associated with HRQOL on the impact and treatment scale. CONCLUSIONS Low HbA1c and male sex are significantly associated with high HRQOL in children aged 10-17 with type 1 diabetes, but the use of diabetes technology is not positively associated with HRQOL. Differences in child- and parent-reported scores imply that parents might both over- and underestimate their child's HRQOL.
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Affiliation(s)
- Heiko Bratke
- Department of Pediatrics, Haugesund Hospital, Fonna Health Trust, Haugesund, Norway
- Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway
- Oslo Diabetes Research Centre, Oslo, Norway
- Department of Research and Innovation, Fonna Health Trust, Haugesund, Norway
| | - Eva Biringer
- Department of Research and Innovation, Fonna Health Trust, Haugesund, Norway
| | - Hanna D. Margeirsdottir
- Oslo Diabetes Research Centre, Oslo, Norway
- Division of Childhood and Adolescent Medicine, Oslo University Hospital, Oslo, Norway
| | - Pål R. Njølstad
- Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway
- Child and Youth Clinic, Haukeland University Hospital, Bergen, Norway
| | - Torild Skrivarhaug
- Oslo Diabetes Research Centre, Oslo, Norway
- Division of Childhood and Adolescent Medicine, Oslo University Hospital, Oslo, Norway
- University of Oslo, Institute of Clinical Medicine, Faculty of Medicine, Oslo, Norway
- The Norwegian Childhood Diabetes Registry, Division of Childhood and Adolescent Medicine, Oslo University Hospital, Oslo, Norway
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24
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Karakilic E, Saygili ES, Silan F, Onduc GG, Agcaoglu U. New results for monogenic diabetes with analysis of causative genes using next-generation sequencing: a tertiary centre experience from Turkey. Int J Diabetes Dev Ctries 2021. [DOI: 10.1007/s13410-021-01027-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
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25
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Pazzagli L, Karampelias C, Selmer R, Andersson O, Cesta CE. Investigating the association between prenatal exposure to folic acid and risk of neonatal diabetes/hyperglycemia and type 1 diabetes: A Norwegian register-based study. Pediatr Diabetes 2021; 22:969-973. [PMID: 34487407 DOI: 10.1111/pedi.13263] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 08/11/2021] [Accepted: 08/25/2021] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND Experimental animal studies suggest a novel role for the folate receptor 1 in β-cell differentiation in the pancreas, with potential implications for glycemic control. We tested the hypothesis of a protective association between prenatal folic acid use and neonatal diabetes or hyperglycemia and type 1 diabetes in an observational cohort study using data from the national population health registers in Norway. METHODS All singleton pregnancies resulting in live births from 2005 to 2018 were identified. Prenatal exposure to folic acid was determined based on maternal report at antenatal care in early pregnancy. Diagnoses of neonatal diabetes, hyperglycemia, and type 1 diabetes for the children were identified. Associations were estimated with logistic regression or Cox proportional hazard model and included crude and adjusted estimates. RESULTS Among 781,567 children, 69% had prenatal exposure to folic acid, 264 were diagnosed with neonatal diabetes or hyperglycemia, and 1390 with type 1 diabetes. Compared to children with no prenatal exposure to folic acid, children with prenatal exposure to folic acid had similar odds of having a neonatal diabetes or hyperglycemia diagnosis (adjusted odds ratio 0.95, 95% confidence interval [CI] 0.72, 1.25) and similar risk of being diagnosed with type 1 diabetes (adjusted hazard ratio 1.05, 95% CI 0.93, 1.18). CONCLUSIONS No association between prenatal folic acid exposure and neonatal diabetes/hyperglycemia or type 1 diabetes was found. These findings do not rule out a translational effect of the experimental results and future studies with longer follow-up and more precise information on the window of prenatal exposure are needed.
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Affiliation(s)
- Laura Pazzagli
- Centre for Pharmacoepidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
| | - Christos Karampelias
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Randi Selmer
- Department of Chronic Diseases and Ageing, Norwegian Institute of Public Health, Oslo, Norway
| | - Olov Andersson
- Department of Cell and Molecular Biology, Karolinska Institutet, Stockholm, Sweden
| | - Carolyn E Cesta
- Centre for Pharmacoepidemiology, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
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Li M, Rivière JB, Polychronakos C. Why all MODY variants are dominantly inherited: a hypothesis. Trends Genet 2021; 38:321-324. [PMID: 34696899 DOI: 10.1016/j.tig.2021.10.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2021] [Revised: 09/24/2021] [Accepted: 10/01/2021] [Indexed: 10/20/2022]
Abstract
Maturity-onset diabetes in the young (MODY) comprises monogenic phenotypes of young-onset, insulinopenic diabetes. All its forms are dominantly inherited. Why? Are the pancreatic β cells only harmed by heterozygous variants? We propose that recessive MODYs do exist but have escaped detection due to lack of family history suggestive of monogenic inheritance.
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Affiliation(s)
- Meihang Li
- Clinical Research Center, Maoming People's Hospital, 101 Weimin Road, Maoming 52500, Guangdong, China; The Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, 308 Ningxia road, Qingdao, Shangdong Province, China; Zhejiang MaiDa Gene Tech, 68 Xinchi road, Zhoushan, Zhejiang Province, China; School of Medicine, Jinan University, 855 Xingye East Road, Panyu, Guangzhou, Guangdong Province, China.
| | - Jean-Baptiste Rivière
- Research Institute of McGill University Health Centre, 1001 Decarie Boulevard, Montreal, QC, Canada.
| | - Constantin Polychronakos
- Zhejiang MaiDa Gene Tech, 68 Xinchi road, Zhoushan, Zhejiang Province, China; Research Institute of McGill University Health Centre, 1001 Decarie Boulevard, Montreal, QC, Canada; Zhejiang University School of Medicine, 866 Yuhangtang road, Hangzhou, Zhejiang Province, China.
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Maturity Onset Diabetes of the Young-New Approaches for Disease Modelling. Int J Mol Sci 2021; 22:ijms22147553. [PMID: 34299172 PMCID: PMC8303136 DOI: 10.3390/ijms22147553] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 07/04/2021] [Accepted: 07/09/2021] [Indexed: 02/08/2023] Open
Abstract
Maturity-onset diabetes of the young (MODY) is a genetically heterogeneous group of monogenic endocrine disorders that is characterised by autosomal dominant inheritance and pancreatic β-cell dysfunction. These patients are commonly misdiagnosed with type 1 or type 2 diabetes, as the clinical symptoms largely overlap. Even though several biomarkers have been tested none of which could be used as single clinical discriminator. The correct diagnosis for individuals with MODY is of utmost importance, as the applied treatment depends on the gene mutation or is subtype-specific. Moreover, in patients with HNF1A-MODY, additional clinical monitoring can be included due to the high incidence of vascular complications observed in these patients. Finally, stratification of MODY patients will enable better and newer treatment options for MODY patients, once the disease pathology for each patient group is better understood. In the current review the clinical characteristics and the known disease-related abnormalities of the most common MODY subtypes are discussed, together with the up-to-date applied diagnostic criteria and treatment options. Additionally, the usage of pluripotent stem cells together with CRISPR/Cas9 gene editing for disease modelling with the possibility to reveal new pathophysiological mechanisms in MODY is discussed.
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Diagnostik, Therapie und Verlaufskontrolle des Diabetes mellitus im Kindes- und Jugendalter. DIABETOLOGE 2021. [DOI: 10.1007/s11428-021-00769-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Liu Y, Xie Z, Sun X, Wang Y, Xiao Y, Luo S, Huang G, Li X, Xia Y, Zhou Z. A new screening strategy and whole-exome sequencing for the early diagnosis of maturity-onset diabetes of the young. Diabetes Metab Res Rev 2021; 37:e3381. [PMID: 32621647 DOI: 10.1002/dmrr.3381] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/29/2019] [Revised: 06/01/2020] [Accepted: 06/30/2020] [Indexed: 12/13/2022]
Abstract
AIMS This study aimed to establish a systematic screening strategy to select candidates for genetic testing among patients with maturity-onset diabetes of the young (MODY) and to accomplish early diagnosis of MODY. MATERIALS AND METHODS We enrolled 1478 sporadic patients from the outpatient department of endocrinology. Out of the1478 patients, 1279 participants were successfully screened according to the "AACM" strategy, which includes the age of onset, autoantibody to islet antigen, C-peptide and metabolic syndrome. Another six probands and their families who fulfilled the common clinical criteria for MODY were also examined for causative gene mutations. Whole-exome sequencing (WES) was performed to examine the mutations. RESULTS A total of 24 out of 1279 sporadic patients with newly diagnosed diabetes were eligible for genetic testing. Mutations were found in 4/24 participants in the cohort, as well as in 2/6 pedigrees. A likely pathogenic alteration, a likely benign alteration and three alterations with uncertain significance were identified with WES. Most of the mutant genes recognised in our trial were not the most common causative genes of MODY, and all of the mutations were specifically reported in Asian patients only, suggesting a unique genetic background of MODY in different ethnicities. CONCLUSIONS In this systematic study of MODY in a new-onset diabetes cohort, MODY cases were incorrectly diagnosed as type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), suggesting that an observant clinician is necessary for early and correct MODY diagnosis. This systematic approach to screening is practical and specific enough to identify patients who are most appropriate for genetic testing.
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Affiliation(s)
- Yue Liu
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University and Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
- Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China
- Foshan Women and Children Hospital, Foshan, Guangdong, China
| | - Zhiguo Xie
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University and Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Xiaoxiao Sun
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University and Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Yanfei Wang
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University and Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Yang Xiao
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University and Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Shuoming Luo
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University and Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Gan Huang
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University and Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Xia Li
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University and Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Ying Xia
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University and Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
| | - Zhiguang Zhou
- Department of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University and Key Laboratory of Diabetes Immunology, Central South University, Ministry of Education, National Clinical Research Center for Metabolic Diseases, Changsha, Hunan, China
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Kim JH, Lee Y, Choi Y, Kim GH, Yoo HW, Choi JH. Etiologic distribution and clinical characteristics of pediatric diabetes in 276 children and adolescents with diabetes at a single academic center. BMC Pediatr 2021; 21:108. [PMID: 33663443 PMCID: PMC7931559 DOI: 10.1186/s12887-021-02575-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Accepted: 02/24/2021] [Indexed: 12/16/2022] Open
Abstract
Background The prevalence of monogenic diabetes is estimated to be 1.1–6.3% of patients with diabetes mellitus (DM) in Europe. The overlapping clinical features of various forms of diabetes make differential diagnosis challenging. Therefore, this study investigated the etiologic distribution and clinical characteristics of pediatric diabetes, including monogenic diabetes, who presented at a single tertiary center over the last 20 years. Methods This study included 276 consecutive patients with DM diagnosed before 18 years of age from January 2000 to December 2019 in Korea. Clinical features, biochemical findings, β-cell autoantibodies, and molecular characteristics were reviewed retrospectively. Results Of the 276 patients, 206 patients (74.6%), 49 patients (17.8%), and 21 patients (7.6%) were diagnosed with type 1 DM, type 2 DM, and clinically suspected monogenic diabetes, respectively. Among 21 patients suspected to have monogenic diabetes, 8 patients had clinical maturity-onset diabetes of the young (MODY), and the remaining 13 patients had other types of monogenic diabetes. Among them, genetic etiologies were identified in 14 patients (5.1%) from 13 families, which included MODY 5, transient neonatal DM, developmental delay, epilepsy, and neonatal diabetes (DEND) syndrome, Wolfram syndrome, Donohue syndrome, immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, Fanconi-Bickel syndrome, Wolcott-Rallison syndrome, cystic fibrosis-related diabetes, and maternally inherited diabetes and deafness. Conclusions Genetically confirmed monogenic diabetes accounted for 5.1% of patients evaluated at a single tertiary center over 20-year period. Based on the findings for our sample, the frequency of mutations in the major genes of MODY appears to be low among pediatric patients in Korea. It is critical to identify the genetic cause of DM to provide appropriate therapeutic options and genetic counseling. Supplementary Information The online version contains supplementary material available at 10.1186/s12887-021-02575-6.
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Affiliation(s)
- Ja Hye Kim
- Department of Pediatrics, Medical Genetics Center, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Yena Lee
- Department of Pediatrics, Medical Genetics Center, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Yunha Choi
- Department of Pediatrics, Medical Genetics Center, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Gu-Hwan Kim
- Medical Genetics Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of Korea
| | - Han-Wook Yoo
- Department of Pediatrics, Medical Genetics Center, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea
| | - Jin-Ho Choi
- Department of Pediatrics, Medical Genetics Center, Asan Medical Center, University of Ulsan College of Medicine, 88, Olympic-Ro 43-Gil, Songpa-Gu, Seoul, 05505, Republic of Korea.
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Aarthy R, Aston-Mourney K, Mikocka-Walus A, Radha V, Amutha A, Anjana RM, Unnikrishnan R, Mohan V. Clinical features, complications and treatment of rarer forms of maturity-onset diabetes of the young (MODY) - A review. J Diabetes Complications 2021; 35:107640. [PMID: 32763092 DOI: 10.1016/j.jdiacomp.2020.107640] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/13/2020] [Revised: 05/21/2020] [Accepted: 05/21/2020] [Indexed: 12/15/2022]
Abstract
Maturity onset diabetes of the young (MODY) is the most common form of monogenic diabetes and is currently believed to have 14 subtypes. While much is known about the common subtypes of MODY (MODY-1, 2, 3 and 5) little is known about its rare subtypes (MODY4, 6-14). With the advent of next-generation sequencing (NGS) there are several reports of the rarer subtypes of MODY emerging from across the world. Therefore, a greater understanding on these rarer subtypes is needed. A search strategy was created, and common databases were searched, and 51 articles finally selected. INS-(MODY10) and ABCC8-(MODY12) mutations were reported in relatively large numbers compared to the other rare subtypes. The clinical characteristics of the rare MODY subtypes exhibited heterogeneity between families reported with the same mutation. Obesity and diabetic ketoacidosis (DKA) were also reported among rarer MODY subtypes which presents as a challenge as these are not part of the original description of MODY by Tattersal and Fajans. The treatment modalities of the rarer subtypes included oral drugs, predominantly sulfonylureas, insulin but also diet alone. Newer drugs like DPP-4 and SGLT2 inhibitors have also been tried as new modes of treatment. The microvascular and macrovascular complications among the patients with various MODY subtypes are less commonly reported. Recently, there is a view that not all the 14 forms of 'MODY' are true MODY and the very existence of some of these rarer subtypes as MODY has been questioned. This scoping review aims to report on the clinical characteristics, treatment and complications of the rarer MODY subtypes published in the literature.
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Affiliation(s)
- Ramasamy Aarthy
- School of Medicine, Deakin University, Australia; Madras Diabetes Research Foundation, Chennai, India
| | | | | | | | | | - Ranjit Mohan Anjana
- Dr Mohan's Diabetes Specialities Centre, Madras Diabetes Research Foundation, Chennai, India
| | - Ranjit Unnikrishnan
- Dr Mohan's Diabetes Specialities Centre, Madras Diabetes Research Foundation, Chennai, India
| | - Viswanathan Mohan
- Dr Mohan's Diabetes Specialities Centre, Madras Diabetes Research Foundation, Chennai, India.
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Katashima R, Matsumoto M, Watanabe Y, Moritani M, Yokota I. Identification of Novel GCK and HNF4α Gene Variants in Japanese Pediatric Patients with Onset of Diabetes before 17 Years of Age. J Diabetes Res 2021; 2021:7216339. [PMID: 34746319 PMCID: PMC8570896 DOI: 10.1155/2021/7216339] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 08/14/2021] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND Maturity-onset diabetes of the young (MODY) is commonly misdiagnosed as type 1 or type 2 diabetes. Common reasons for misdiagnosis are related to limitations in genetic testing. A precise molecular diagnosis is essential for the optimal treatment of patients and allows for early diagnosis of their asymptomatic family members. OBJECTIVE The aim of this study was to identify rare monogenic variants of common MODY genes in Japanese pediatric patients. METHODS We investigated 45 Japanese pediatric patients based on the following clinical criteria: development of diabetes before 17 years of age, a family history of diabetes, testing negative for glutamate decarboxylase-65 (GAD 65) antibodies and insulinoma-2-associated autoantibodies (IA-2A), no significant obesity, and evidence of endogenous insulin production. Genetic screening for MODY1 (HNF4α), MODY2 (GCK), MODY3 (HNF1α), and MODY5 (HNF1β) was performed by direct sequencing followed by multiplex ligation amplification assays. RESULTS We identified 22 missense variants (3 novel variants) in 27 patients (60.0%) in the GCK, HNF4α, and HNF1α genes. We also detected a whole exon deletion in the HNF1β gene and an exon 5-6 aberration in the GCK gene, each in one proband (4.4%). There were a total of 29 variations (64.4%), giving a relative frequency of 53.3% (24/45) for GCK, 2.2% (1/45) for HNF4α, 6.7% (3/45) for HNF1α, and 2.2% (1/45) for HNF1β genes. CONCLUSIONS Clinicians should consider collecting and assessing detailed clinical information, especially regarding GCK gene variants, in young antibody-negative patients with diabetes. Correct molecular diagnosis of MODY better predicts the clinical course of diabetes and facilitates individualized management.
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Affiliation(s)
- Rumi Katashima
- Laboratory for Pediatric Genome Medicine, Department of Clinical Research, National Hospital Organization Shikoku Medical Center for Children and Adults, 2-1-1 Senyu-cho, Zentsuji City, Kagawa 765-8507, Japan
| | - Mari Matsumoto
- Laboratory for Pediatric Genome Medicine, Department of Clinical Research, National Hospital Organization Shikoku Medical Center for Children and Adults, 2-1-1 Senyu-cho, Zentsuji City, Kagawa 765-8507, Japan
- Department of Endocrinology and Metabolism, Faculty of Medicine, Kagawa University, 1750-1, Miki-cho, Kita-gun, Kagawa 761-0793, Japan
| | - Yuka Watanabe
- Laboratory for Pediatric Genome Medicine, Department of Clinical Research, National Hospital Organization Shikoku Medical Center for Children and Adults, 2-1-1 Senyu-cho, Zentsuji City, Kagawa 765-8507, Japan
| | - Maki Moritani
- Laboratory for Pediatric Genome Medicine, Department of Clinical Research, National Hospital Organization Shikoku Medical Center for Children and Adults, 2-1-1 Senyu-cho, Zentsuji City, Kagawa 765-8507, Japan
| | - Ichiro Yokota
- Laboratory for Pediatric Genome Medicine, Department of Clinical Research, National Hospital Organization Shikoku Medical Center for Children and Adults, 2-1-1 Senyu-cho, Zentsuji City, Kagawa 765-8507, Japan
- Department of Pediatric Endocrinology and Metabolism, National Hospital Organization Shikoku Medical Center for Children and Adults, 2-1-1, Senyu-cho, Zentsuji City, Kagawa 765-8507, Japan
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The epidemiology, molecular pathogenesis, diagnosis, and treatment of maturity-onset diabetes of the young (MODY). Clin Diabetes Endocrinol 2020; 6:20. [PMID: 33292863 PMCID: PMC7640483 DOI: 10.1186/s40842-020-00112-5] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/17/2020] [Accepted: 10/26/2020] [Indexed: 12/18/2022] Open
Abstract
Background The most common type of monogenic diabetes is maturity-onset diabetes of the young (MODY), a clinically and genetically heterogeneous group of endocrine disorders that affect 1–5% of all patients with diabetes mellitus. MODY is characterized by autosomal dominant inheritance but de novo mutations have been reported. Clinical features of MODY include young-onset hyperglycemia, evidence of residual pancreatic function, and lack of beta cell autoimmunity or insulin resistance. Glucose-lowering medications are the main treatment options for MODY. The growing recognition of the clinical and public health significance of MODY by clinicians, researchers, and governments may lead to improved screening and diagnostic practices. Consequently, this review article aims to discuss the epidemiology, pathogenesis, diagnosis, and treatment of MODY based on relevant literature published from 1975 to 2020. Main body The estimated prevalence of MODY from European cohorts is 1 per 10,000 in adults and 1 per 23,000 in children. Since little is known about the prevalence of MODY in African, Asian, South American, and Middle Eastern populations, further research in non-European cohorts is needed to help elucidate MODY’s exact prevalence. Currently, 14 distinct subtypes of MODY can be diagnosed through clinical assessment and genetic analysis. Various genetic mutations and disease mechanisms contribute to the pathogenesis of MODY. Management of MODY is subtype-specific and includes diet, oral antidiabetic drugs, or insulin. Conclusions Incidence and prevalence estimates for MODY are derived from epidemiologic studies of young people with diabetes who live in Europe, Australia, and North America. Mechanisms involved in the pathogenesis of MODY include defective transcriptional regulation, abnormal metabolic enzymes, protein misfolding, dysfunctional ion channels, or impaired signal transduction. Clinicians should understand the epidemiology and pathogenesis of MODY because such knowledge is crucial for accurate diagnosis, individualized patient management, and screening of family members.
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Genotype-Phenotype Characteristics of Turkish Children With Glucokinase Mutations Associated Maturity-Onset Diabetes of the Young. Indian Pediatr 2020. [DOI: 10.1007/s13312-020-2032-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Abstract
Neonatal diabetes (ND) appears during the first months of life and is caused by a single gene mutation. It is heterogenous and very different compared to other forms of multi-factorial or polygenic diabetes. Clinically, this form is extremely severe, however, early genetic diagnosis is pivotal for successful therapy. A large palette of genes is demonstrated to be a cause of ND, however, the mechanisms of permanent hyperglycemia are different. This review will give an overview of more frequent genetic mutations causing ND, including the function of the mutated genes and the specific therapy for certain sub-forms.
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Affiliation(s)
- M Kocova
- Medical Faculty, University Cyril and Methodius, Skopje, Republic of Macedonia
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Zmyslowska A, Stanczak M, Nowicka Z, Waszczykowska A, Baranska D, Fendler W, Borowiec M, Młynarski W. Serum microRNA as indicators of Wolfram syndrome's progression in neuroimaging studies. BMJ Open Diabetes Res Care 2020; 8:8/2/e001379. [PMID: 33132210 PMCID: PMC7607591 DOI: 10.1136/bmjdrc-2020-001379] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 09/14/2020] [Accepted: 09/14/2020] [Indexed: 12/19/2022] Open
Abstract
INTRODUCTION Patients with the ultra-rare Wolfram syndrome (WFS) develop insulin-dependent diabetes and progressive neurodegeneration. The aim of the study was to quantify microRNAs (miRNAs) in sera from patients with WFS, correlate their expression with neurological imaging over time and compare miRNA levels with those observed in patients with type 1 diabetes mellitus (T1DM). RESEARCH DESIGN AND METHODS We quantified miRNA expression (Qiagen, Germany) in two groups of patients: with WFS at study entry (n=14) and after 2 years of follow-up and in 15 glycated hemoglobin-matched (p=0.72) patients with T1DM. RESULTS We observed dynamic changes in the expression of multiple miRNAs in patients with WFS parallel to disease progression and in comparison to the T1DM patients group. Among miRNAs that differed between baseline and follow-up WFS samples, the level of 5 increased over time (miR-375, miR-30d-5p, miR-30e-30, miR-145-5p and miR-193a-5p) and was inversely correlated with macular average thickness, while the expression of 2 (let-7g-5p and miR-22-3p) decreased and was directly correlated with neuroimaging indicators of neurodegeneration. CONCLUSIONS Our findings show for the first time that serum miRNAs can be used as easily accessible indicators of disease progression in patients with WFS, potentially facilitating clinical trials on mitigating neurodegeneration.
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Affiliation(s)
| | - Marcin Stanczak
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland
| | - Zuzanna Nowicka
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland
| | - Arleta Waszczykowska
- Department of Ophthalmology and Vision Rehabilitation, Medical University of Lodz, Lodz, Poland
| | - Dobromila Baranska
- Department of Diagnostic Imaging, Polish Mother's Memorial Hospital Research Institute, Lodz, Poland
| | - Wojciech Fendler
- Department of Biostatistics and Translational Medicine, Medical University of Lodz, Lodz, Poland
- Department of Radiation Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA
| | - Maciej Borowiec
- Department of Clinical Genetics, Medical University of Lodz, Lodz, Poland
| | - Wojciech Młynarski
- Department of Pediatrics, Oncology and Hematology, Medical University of Lodz, Lodz, Poland
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Sarmadi A, Mohammadi A, Tabatabaei F, Nouri Z, Chaleshtori MH, Tabatabaiefar MA. Molecular Genetic Study in a Cohort of Iranian Families Suspected to Maturity-Onset Diabetes of the Young, Reveals a Recurrent Mutation and a High-Risk Variant in the CEL Gene. Adv Biomed Res 2020; 9:25. [PMID: 33072637 PMCID: PMC7532821 DOI: 10.4103/abr.abr_18_20] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 03/01/2020] [Accepted: 04/07/2020] [Indexed: 01/14/2023] Open
Abstract
Background Diabetes mellitus (DM) is a group of metabolic disorders in the body, accompanied with increasing blood sugar levels. Diabetes is classified into three groups: Type 1 DM (T1DM), Type 2 DM (T2DM), and monogenic diabetes. Maturity-onset diabetes of the young (MODY) is a monogenic diabetes that is frequently mistaken for T1D or T2D. The aim of this study was to diagnose MODY and its subtype frequency in a diabetic population in Iran. Materials and Methods In this study among ten diabetic families that were highly suspected to MODY by nongenetic biomarkers and without any pathogenic mutation in GCK and HNF1A genes, two patients from two unrelated families were examined via whole-exome sequencing (WES) in order to detect the causative gene of diabetes. Co-segregation analysis of the identified variant was performed using Sanger sequencing. Results In this study, no pathogenic variant was found in GCK and HNF1A genes (MODY2 and MODY3), while these two types of MODY were introduced as the most frequent in other studies. By using WES, a pathogenic variant (p.I488T) was found in one of the patients in CEL gene causing MODY8 that its frequency is very rare in other studied populations. A high-risk variant associated with diabetes was found in another patient. Conclusion WES was applied in this study to reveal the cause of MODY in 1 family. This pathogenic mutation was previously reported as a disease causing mutation.
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Affiliation(s)
- Akram Sarmadi
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Aliasgar Mohammadi
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Fatemeh Tabatabaei
- Isfahan Endocrine and Metabolism Research Center, Isfahan University of Medical Science, Isfahan, Iran
| | - Zahra Nouri
- Department of Medical Biotechnology, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Morteza Hashemzadeh Chaleshtori
- Cellular and Molecular Research Center, Basic Health Sciences Institute, Shahrekord University of Medical Sciences, Shahrekord, Iran
| | - Mohammad Amin Tabatabaiefar
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran.,Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
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Alhaidan Y, Christesen HT, Højlund K, Al Balwi MA, Brusgaard K. A novel gene in early childhood diabetes: EDEM2 silencing decreases SLC2A2 and PXD1 expression, leading to impaired insulin secretion. Mol Genet Genomics 2020; 295:1253-1262. [PMID: 32556999 DOI: 10.1007/s00438-020-01695-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2019] [Accepted: 06/08/2020] [Indexed: 11/29/2022]
Abstract
Monogenic diabetes is a rare type of diabetes resulting from mutations in a single gene. To date, most cases remain genetically unexplained, posing a challenge for accurate diabetes treatment, which leads to on a molecular diagnosis. Therefore, a trio exome scan was performed in a lean, nonsyndromic Caucasian girl with diabetes onset at 2½ years who was negative for autoantibodies. The lean father had diabetes from age 11 years. A novel heterozygous mutation in EDEM2, c.1271G > A; p.Arg424His, was found in the proband and father. Downregulation of Edem2 in rat RIN-m β-cells resulted in a decrease in insulin genes Ins1 to 67.9% (p = 0.006) and Ins2 to 16.8% (p < 0.001) and reduced insulin secretion by 60.4% (p = 0.0003). Real-time PCR revealed a major disruption of endocrine pancreas-specific genes, including Glut2 and Pxd1, with mRNA suppression to 54% (p < 0.001) and 85.7% (p = 0.01), respectively. No other expression changes related to stress or apoptotic genes were observed. Extended clinical follow-up involving ten family members showed that two healthy individuals carried the same mutation with no sign of diabetes in the clinical screen except for a slight increase in IA-2 antibody in one of them, suggesting incomplete penetrance. In conclusion, we describe EDEM2 as a likely/potential novel diabetes gene, in which inhibition in vitro reduces the expression of β-cell genes involved in the glucose-stimulated insulin secretion (GSIS) pathway, leading to an overall suppression of insulin secretion but not apoptosis.
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Affiliation(s)
- Yazeid Alhaidan
- Department of Clinical Genetics, Odense University Hospital, J.B. Windsløws Vej 4, 5000, Odense, Denmark. .,Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, 5000, Odense C, Denmark. .,Department of Medical Genomics Research, King Abdullah International Medical Research Center, Riyadh, 11426, Saudi Arabia. .,King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
| | - Henrik Thybo Christesen
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, 5000, Odense C, Denmark.,Hans Christian Andersen Children's Hospital, Odense University Hospital, 5000, Odense C, Denmark.,Odense Pancreases Center, Odense C, Denmark
| | - Kurt Højlund
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, 5000, Odense C, Denmark.,Steno Diabetes Center Odense, Odense University Hospital, 5000, Odense, Denmark
| | - Mohammed A Al Balwi
- Department of Medical Genomics Research, King Abdullah International Medical Research Center, Riyadh, 11426, Saudi Arabia.,King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Klaus Brusgaard
- Department of Clinical Genetics, Odense University Hospital, J.B. Windsløws Vej 4, 5000, Odense, Denmark.,Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, 5000, Odense C, Denmark.,Near East University, Nicosia, Cyprus
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39
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Arslanian S, El ghormli L, Haymond MH, Chan CL, Chernausek SD, Gandica RG, Gubitosi-Klug R, Levitsky LL, Siska M, Willi SM. Beta cell function and insulin sensitivity in obese youth with maturity onset diabetes of youth mutations vs type 2 diabetes in TODAY: Longitudinal observations and glycemic failure. Pediatr Diabetes 2020; 21:575-585. [PMID: 32064729 PMCID: PMC7654712 DOI: 10.1111/pedi.12998] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 01/22/2020] [Accepted: 01/29/2020] [Indexed: 12/25/2022] Open
Abstract
OBJECTIVE In treatment options for type 2 diabetes in adolescents and youth (TODAY), 4.5% of obese youth clinically diagnosed with type 2 diabetes (T2D) had genetic variants consistent with maturity onset diabetes of youth (MODY) diagnosis. The course of IS and β-cell function in obese youth with MODY remains unknown. In this secondary analysis, we examined IS and β-cell function in MODY vs. non-MODY obese youth at randomization and over time. METHODS Genetic data in TODAY included 426 non-MODY (T2D) and 22 MODY youth (7 glucokinase MODY mutation positive [GCK-MODY], 12 hepatocyte nuclear factor MODY mutation positive [HNF-MODY], 2 Insulin gene mutation [insulin (INS)-MODY], and 1 Kruppel-like factor 11 [KLF11-MODY]). Oral glucose tolerance test (OGTT)-derived IS, C-peptide index, and β-cell function relative to IS oral disposition index (oDI) was measured at randomization, and over 24 months in addition to total and high-molecular-weight adiponectin (HMWA). RESULTS At randomization, IS, total adiponectin, and HMWA were significantly higher in the two MODY groups than in non-MODY. β-cell function measured by C-peptide oDI was 3-fold higher in GCK-MODY than in HNF-MODY and 1.5-fold higher than non-MODY (P for both <.05). Glycemic failure rate was 75.0% in HNF-MODY, 46.9% in non-MODY, and zero in GCK-MODY youth. While the changes in IS and oDI were not different among the three groups in the first 6 months, IS improved from 6 to 24 months in HNF-MODY vs GCK-MODY youth. CONCLUSIONS In TODAY, β-cell function at randomization was worse in obese HNF-MODY youth compared with GCK-MODY youth, while insulin sensitivity was worse in non-MODY compared with the other two MODY groups. Over time, IS showed the greatest improvement in HNF-MODY youth. This raises the possibility that TODAY therapeutic modalities of insulin sensitization in these obese HNF-MODY youth may have played a beneficial role.
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Affiliation(s)
- Silva Arslanian
- UPMC Children’s Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Laure El ghormli
- George Washington University Biostatistics Center, Rockville, Maryland
| | | | | | | | | | | | | | | | - Steven M. Willi
- Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania
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40
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Stankute I, Verkauskiene R, Blouin JL, Klee P, Dobrovolskiene R, Danyte E, Dirlewanger M, Santoni F, Razanskaite-Virbickiene D, Marciulionyte D, Jasinskiene E, Mockeviciene G, Schwitzgebel VM. 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 2020; 69:1065-1071. [PMID: 32086287 DOI: 10.2337/db19-0974] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Accepted: 01/27/2020] [Indexed: 11/13/2022]
Abstract
Identifying gene variants causing monogenic diabetes (MD) increases understanding of disease etiology and allows for implementation of precision therapy to improve metabolic control and quality of life. Here, we aimed to assess the prevalence of MD in youth with diabetes in Lithuania, uncover potential diabetes-related gene variants, and prospectively introduce precision treatment. First, we assessed all pediatric and most young-adult patients with diabetes in Lithuania (n = 1,209) for diabetes-related autoimmune antibodies. We then screened all antibody-negative patients (n = 153) using targeted high-throughput sequencing of >300 potential candidate genes. In this group, 40.7% had MD, with the highest percentage (100%) in infants (diagnosis at ages 0-12 months), followed by those diagnosed at ages >1-18 years (40.3%) and >18-25 years (22.2%). The overall prevalence of MD in youth with diabetes in Lithuania was 3.5% (1.9% for GCK diabetes, 0.7% for HNF1A, 0.2% for HNF4A and ABCC8, 0.3% for KCNJ11, and 0.1% for INS). Furthermore, we identified likely pathogenic variants in 11 additional genes. Microvascular complications were present in 26% of those with MD. Prospective treatment change was successful in >50% of eligible candidates, with C-peptide >252 pmol/L emerging as the best prognostic factor.
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Affiliation(s)
- Ingrida Stankute
- Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Rasa Verkauskiene
- Institute of Endocrinology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Jean-Louis Blouin
- Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland
- Department of Genetic Medicine and Laboratory, University Hospitals of Geneva, Geneva, Switzerland
| | - Philippe Klee
- Pediatric Endocrine and Diabetes Unit, Department of Pediatrics, Gynecology and Obstetrics, University Hospitals of Geneva, Geneva, Switzerland
- Diabetes Center of the Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | | | - Evalda Danyte
- Institute of Endocrinology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Mirjam Dirlewanger
- Pediatric Endocrine and Diabetes Unit, Department of Pediatrics, Gynecology and Obstetrics, University Hospitals of Geneva, Geneva, Switzerland
- Diabetes Center of the Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Federico Santoni
- Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | | | - Dale Marciulionyte
- Institute of Endocrinology, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Edita Jasinskiene
- Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Giedre Mockeviciene
- Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
| | - Valerie M Schwitzgebel
- Pediatric Endocrine and Diabetes Unit, Department of Pediatrics, Gynecology and Obstetrics, University Hospitals of Geneva, Geneva, Switzerland
- Diabetes Center of the Faculty of Medicine, University of Geneva, Geneva, Switzerland
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41
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Yahaya TO, Ufuoma SB. Genetics and Pathophysiology of Maturity-onset Diabetes of the Young (MODY): A Review of Current Trends. Oman Med J 2020; 35:e126. [PMID: 32489678 PMCID: PMC7254248 DOI: 10.5001/omj.2020.44] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2018] [Accepted: 02/04/2019] [Indexed: 02/05/2023] Open
Abstract
Single gene mutations have been implicated in the pathogenesis of a form of diabetes mellitus (DM) known as the maturity-onset diabetes of the young (MODY). However, there are diverse opinions on the suspect genes and pathophysiology, necessitating the need to review and communicate the genes to raise public awareness. We used the Google search engine to retrieve relevant information from reputable sources such as PubMed and Google Scholar. We identified 14 classified MODY genes as well as three new and unclassified genes linked with MODY. These genes are fundamentally embedded in the beta cells, the most common of which are HNF1A, HNF4A, HNF1B, and GCK genes. Mutations in these genes cause β-cell dysfunction, resulting in decreased insulin production and hyperglycemia. MODY genes have distinct mechanisms of action and phenotypic presentations compared with type 1 and type 2 DM and other forms of DM. Healthcare professionals are therefore advised to formulate drugs and treatment based on the causal genes rather than the current generalized treatment for all types of DM. This will increase the effectiveness of diabetes drugs and treatment and reduce the burden of the disease.
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Affiliation(s)
- Tajudeen O. Yahaya
- Department of Biology, Federal University Birnin Kebbi, Kebbi State, Nigeria
| | - Shemishere B. Ufuoma
- Department of Biochemistry and Molecular Biology, Federal University Birnin Kebbi, Kebbi State, Nigeria
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42
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Li M, Wang S, Xu K, Chen Y, Fu Q, Gu Y, Shi Y, Zhang M, Sun M, Chen H, Han X, Li Y, Tang Z, Cai L, Li Z, Shi Y, Yang T, Polychronakos C. 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. [PMID: 31658956 DOI: 10.2337/db19-0510] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/21/2019] [Accepted: 10/20/2019] [Indexed: 12/13/2022]
Abstract
It is estimated that ∼1% of European ancestry patients clinically diagnosed with type 1 diabetes (T1D) actually have monogenic forms of the disease. Because of the much lower incidence of true T1D in East Asians, we hypothesized that the percentage would be much higher. To test this, we sequenced the exome of 82 Chinese Han patients clinically diagnosed with T1D but negative for three autoantibodies. Analysis focused on established or proposed monogenic diabetes genes. We found credible mutations in 18 of the 82 autoantibody-negative patients (22%). All mutations had consensus pathogenicity support by five algorithms. As in Europeans, the most common gene was HNF1A (MODY3), in 6 of 18 cases. Surprisingly, almost as frequent were diallelic mutations in WFS1, known to cause Wolfram syndrome but also described in nonsyndromic cases. Fasting C-peptide varied widely and was not predictive. Given the 27.4% autoantibody negativity in Chinese and 22% mutation rate, we estimate that ∼6% of Chinese with a clinical T1D diagnosis have monogenic diabetes. Our findings support universal sequencing of autoantibody-negative cases as standard of care in East Asian patients with a clinical T1D diagnosis. Nonsyndromic diabetes with WSF1 mutations is not rare in Chinese. Its response to alternative treatments should be investigated.
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Affiliation(s)
- Meihang Li
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- The Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, China
- Zhejiang MaiDa Gene Tech Co., Ltd., Zhoushan, China
| | - Sihua Wang
- Zhejiang MaiDa Gene Tech Co., Ltd., Zhoushan, China
| | - Kuanfeng Xu
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yang Chen
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qi Fu
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yong Gu
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yun Shi
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Mei Zhang
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Min Sun
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Heng Chen
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xiuqun Han
- Zhejiang MaiDa Gene Tech Co., Ltd., Zhoushan, China
| | - Yangxi Li
- Zhejiang MaiDa Gene Tech Co., Ltd., Zhoushan, China
- The Research Institute of the McGill University Health Centre, Montreal, Canada
| | - Zhoukai Tang
- Zhejiang MaiDa Gene Tech Co., Ltd., Zhoushan, China
| | - Lejing Cai
- Zhejiang MaiDa Gene Tech Co., Ltd., Zhoushan, China
| | - Zhiqiang Li
- The Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, China
| | - Yongyong Shi
- The Biomedical Sciences Institute of Qingdao University (Qingdao Branch of SJTU Bio-X Institutes), Qingdao University, Qingdao, China
| | - Tao Yang
- Department of Endocrinology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Constantin Polychronakos
- Zhejiang MaiDa Gene Tech Co., Ltd., Zhoushan, China
- The Research Institute of the McGill University Health Centre, Montreal, Canada
- Children's Hospital of Zhejiang University School of Medicine, Hangzhou, China
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43
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Dallali H, Pezzilli S, Hechmi M, Sallem OK, Elouej S, Jmel H, Ben Halima Y, Chargui M, Gharbi M, Mercuri L, Alberico F, Mazza T, Bahlous A, Ben Ahmed M, Jamoussi H, Abid A, Trischitta V, Abdelhak S, Prudente S, Kefi R. Genetic characterization of suspected MODY patients in Tunisia by targeted next-generation sequencing. Acta Diabetol 2019; 56:515-523. [PMID: 30656436 DOI: 10.1007/s00592-018-01283-5] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2018] [Accepted: 12/25/2018] [Indexed: 01/05/2023]
Abstract
AIMS Maturity Onset Diabetes of the Young (MODY) is a monogenic form of diabetes with autosomal dominant inheritance pattern. The diagnosis of MODY and its subtypes is based on genetic testing. Our aim was investigating MODY by means of next-generation sequencing in the Tunisian population. METHODS We performed a targeted sequencing of 27 genes known to cause monogenic diabetes in 11 phenotypically suspected Tunisian patients. We retained genetic variants passing filters of frequency in public databases as well as their probable effects on protein structures and functions evaluated by bioinformatics prediction tools. RESULTS Five heterozygous variants were found in four patients. They include two mutations in HNF1A and GCK that are the causative genes of the two most prevalent MODY subtypes described in the literature. Other possible mutations, including novel frameshift and splice-site variants were identified in ABCC8 gene. CONCLUSIONS Our study is the first to investigate the clinical application of targeted next-generation sequencing for the diagnosis of MODY in Africa. The combination of this approach with a filtering/prioritization strategy made a step towards the identification of MODY mutations in the Tunisian population.
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Affiliation(s)
- Hamza Dallali
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, BP 74, 13 Place Pasteur, 1002, Tunis, Tunisia
- National Institute of Applied Sciences and Technology, University of Carthage, Tunis, Tunisia
| | - Serena Pezzilli
- Research Unit of Metabolic and Cardiovascular Diseases, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
- Department of Experimental Medicine, Sapienza University, Rome, Italy
| | - Meriem Hechmi
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, BP 74, 13 Place Pasteur, 1002, Tunis, Tunisia
- National Institute of Applied Sciences and Technology, University of Carthage, Tunis, Tunisia
| | | | - Sahar Elouej
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, BP 74, 13 Place Pasteur, 1002, Tunis, Tunisia
- Faculty of Medicine La Timone, INSERM, GMGF, Aix Marseille University, 27 bd Jean Moulin, 13385, Marseille, France
| | - Haifa Jmel
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, BP 74, 13 Place Pasteur, 1002, Tunis, Tunisia
- Faculty of Sciences of Bizerte, University of Carthage, Tunis, Tunisia
| | - Yosra Ben Halima
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, BP 74, 13 Place Pasteur, 1002, Tunis, Tunisia
- University of Tunis El Manar, El Manar I, 2092, Tunis, Tunisia
| | - Mariem Chargui
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, BP 74, 13 Place Pasteur, 1002, Tunis, Tunisia
| | - Mariem Gharbi
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, BP 74, 13 Place Pasteur, 1002, Tunis, Tunisia
| | - Luana Mercuri
- Research Unit of Metabolic and Cardiovascular Diseases, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Federica Alberico
- Research Unit of Metabolic and Cardiovascular Diseases, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Tommaso Mazza
- Unit of Bioinformatics, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Afaf Bahlous
- Central Laboratory of Medical Biology, Institut Pasteur de Tunis, BP 74, 13 Place Pasteur, 1002, Tunis, Tunisia
| | - Melika Ben Ahmed
- Laboratory of Transmission, Control and Immunobiology of Infections, Institut Pasteur de Tunis, BP 74, 13 Place Pasteur, 1002, Tunis, Tunisia
| | - Henda Jamoussi
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, BP 74, 13 Place Pasteur, 1002, Tunis, Tunisia
- Research Unit on Obesity, National Institute of Nutrition and Food Technology, 11 rue Jebel Lakhdar, Bab Saadoun, 1007, Tunis, Tunisia
| | - Abdelmajid Abid
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, BP 74, 13 Place Pasteur, 1002, Tunis, Tunisia
- Research Unit on Obesity, National Institute of Nutrition and Food Technology, 11 rue Jebel Lakhdar, Bab Saadoun, 1007, Tunis, Tunisia
| | - Vincenzo Trischitta
- Research Unit of Metabolic and Cardiovascular Diseases, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
- Department of Experimental Medicine, Sapienza University, Rome, Italy
| | - Sonia Abdelhak
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, BP 74, 13 Place Pasteur, 1002, Tunis, Tunisia
- University of Tunis El Manar, El Manar I, 2092, Tunis, Tunisia
| | - Sabrina Prudente
- Research Unit of Metabolic and Cardiovascular Diseases, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
| | - Rym Kefi
- Laboratory of Biomedical Genomics and Oncogenetics, Institut Pasteur de Tunis, BP 74, 13 Place Pasteur, 1002, Tunis, Tunisia.
- University of Tunis El Manar, El Manar I, 2092, Tunis, Tunisia.
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Sanyoura M, Letourneau L, Knight Johnson AE, Del Gaudio D, Greeley SAW, Philipson LH, Naylor RN. GCK-MODY in the US Monogenic Diabetes Registry: Description of 27 unpublished variants. Diabetes Res Clin Pract 2019; 151:231-236. [PMID: 31063852 PMCID: PMC6544496 DOI: 10.1016/j.diabres.2019.04.017] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 03/25/2019] [Accepted: 04/12/2019] [Indexed: 12/12/2022]
Abstract
We report on 134 unique GCK variants in 217 families, including 27 unpublished variants, identified in the US Monogenic Diabetes Registry in the last decade. Using ACMG guidelines, 26% were pathogenic, 56% likely pathogenic and 18% were of uncertain significance. Those with pathogenic variants had clinical features consistent with GCK-MODY.
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Affiliation(s)
- May Sanyoura
- Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, The University of Chicago, 5841 S. Maryland Ave., MC 1027, Chicago, IL 60637, USA.
| | - Lisa Letourneau
- Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, The University of Chicago, 5841 S. Maryland Ave., MC 1027, Chicago, IL 60637, USA
| | - Amy E Knight Johnson
- Department of Human Genetics, University of Chicago Genetic Services Laboratory, The University of Chicago, Chicago, IL, USA
| | - Daniela Del Gaudio
- Department of Human Genetics, University of Chicago Genetic Services Laboratory, The University of Chicago, Chicago, IL, USA
| | - Siri Atma W Greeley
- Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, The University of Chicago, 5841 S. Maryland Ave., MC 1027, Chicago, IL 60637, USA
| | - Louis H Philipson
- Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, The University of Chicago, 5841 S. Maryland Ave., MC 1027, Chicago, IL 60637, USA
| | - Rochelle N Naylor
- Section of Adult and Pediatric Endocrinology, Diabetes, and Metabolism, The University of Chicago, 5841 S. Maryland Ave., MC 1027, Chicago, IL 60637, USA
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45
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Park SS, Jang SS, Ahn CH, Kim JH, Jung HS, Cho YM, Lee YA, Shin CH, Chae JH, Kim JH, Choi SH, Jang HC, Bae JC, Won JC, Kim SH, Kim JI, Kwak SH, Park KS. Identifying Pathogenic Variants of Monogenic Diabetes Using Targeted Panel Sequencing in an East Asian Population. J Clin Endocrinol Metab 2019; 104:4188-4198. [PMID: 30977832 DOI: 10.1210/jc.2018-02397] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Accepted: 04/08/2019] [Indexed: 02/05/2023]
Abstract
PURPOSE Monogenic diabetes is a specific type of diabetes in which precision medicine could be applied. In this study, we used targeted panel sequencing to investigate pathogenic variants in Korean patients clinically suspected to have monogenic diabetes. METHODS The eligibility criteria for inclusion were non-type 1 diabetes patients with an age of onset ≤ 30 years and a BMI (body mass index) ≤ 30 kg/m2. Among the 2,090 non-type 1 diabetes patients, 109 were suspected to have monogenic diabetes and subjected to genetic testing. We analyzed 30 monogenic diabetes genes using targeted panel sequencing. The pathogenicity of the genetic variants was evaluated according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology guidelines. RESULTS Among the 109 suspected monogenic diabetes patients, 23 (21.1%) patients harbored pathogenic/likely pathogenic variants. A total of 14 pathogenic/likely pathogenic variants of common maturity onset diabetes of the young (MODY) genes were identified in GCK, HNF1A, HNF4A, and HNF1B. Other pathogenic/likely pathogenic variants were identified in WFS1, INS, ABCC8 and FOXP3. The mitochondrial DNA 3243 A>G variant was identified in five participants. Patients with pathogenic/likely pathogenic variants had a significantly higher MODY probability, a lower BMI, and a lower C-peptide level than those without pathogenic/likely pathogenic variants (P=0.007, P=0.001, and P=0.012, respectively). CONCLUSIONS Using targeted panel sequencing followed by pathogenicity evaluation, we were able to make molecular genetic diagnoses for 23 (21.1%) suspected monogenic diabetes patients. Lower BMI, higher MODY probability, and lower C-peptide levels were characteristics of these participants.
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Affiliation(s)
- Seung Shin Park
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Se Song Jang
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Republic of Korea
| | - Chang Ho Ahn
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Jung Hee Kim
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Hye Seung Jung
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Young Min Cho
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Young Ah Lee
- Department of Pediatrics, Seoul National University Hospital, Seoul, Republic of Korea
| | - Choong Ho Shin
- Department of Pediatrics, Seoul National University Hospital, Seoul, Republic of Korea
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jong Hee Chae
- Department of Pediatrics, Seoul National University Hospital, Seoul, Republic of Korea
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Jae Hyun Kim
- Department of Pediatrics, Seoul National University Bundang Hospital, Seongnam, Republic of Korea
| | - Sung Hee Choi
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Internal Medicine, Seoul National University Bundang Hospital
| | - Hak C Jang
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Internal Medicine, Seoul National University Bundang Hospital
| | - Jee Cheol Bae
- Department of Internal Medicine, Samsung Changwon Hospital, Changwon, Republic of Korea
| | - Jong Cheol Won
- Department of Internal Medicine, Sanggye Paik Hospital, Seoul, Republic of Korea
| | - Sung-Hoon Kim
- Department of Internal Medicine, Cheil General Hospital & Women's Healthcare Center, Seoul, Republic of Korea
- Department of Internal Medicine, Dankook University College of Medicine, Seoul, Republic of Korea
| | - Jong-Il Kim
- Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Republic of Korea
- Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Republic of Korea
- Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Republic of Korea
| | - Soo Heon Kwak
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
| | - Kyong Soo Park
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Republic of Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea
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Warncke K, Kummer S, Raile K, Grulich-Henn J, Woelfle J, Steichen E, Prinz N, Holl RW. Frequency and Characteristics of MODY 1 (HNF4A Mutation) and MODY 5 (HNF1B Mutation): Analysis From the DPV Database. J Clin Endocrinol Metab 2019; 104:845-855. [PMID: 30535056 DOI: 10.1210/jc.2018-01696] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/08/2018] [Accepted: 12/05/2018] [Indexed: 12/30/2022]
Abstract
OBJECTIVE To characterize the initial presentation and clinical course of patients with hepatocyte nuclear factor (HNF) 4A‒ and HNF1B‒MODY in a multinational registry. DESIGN, SETTING, AND PARTICIPANTS Within the Diabetes Patienten Verlaufsdokumentation (DPV) registry, 44 patients with HNF4A- and 35 patients with HNF1B-MODY were characterized and compared with patients <20 years old with type 1 diabetes (T1D)/type 2 diabetes (T2D). MAIN OUTCOME MEASURE Clinical and laboratory parameters, therapy, metabolic control, and extrapancreatic symptoms in patients with HNF1B-MODY. RESULTS Patients with both MODY types were significantly older than patients with T1D at diagnosis (HNF4A, 13.8 years, and HNF1B, 13.5 years, vs T1D, 8.8 years; P < 0.0001). Mean C-peptide at diagnosis was higher for HNF4A-MODY than for T1D (1.8 vs 0.9 ng/mL; P < 0.01); 36.4% of patients with HNF4A-MODY and 65.7% of patients with HNF1B-MODY were treated with insulin, whereas 20.5% and 8.6% received oral antidiabetics only (P < 0.05 and P < 0.01 vs T2D). At the most recent visit, glycated hemoglobin levels were lower in HNF4A- and HNF1B-MODY (mean, 6.5% and 6.1%) than in T1D (7.9%; P < 0.0001). In 40% of patients with HNF1B-MODY, extrapancreatic symptoms were reported. Several clinical predictors previously described to differentiate between MODY and T1D or T2D were revalidated by logistic regression analyses in this cohort. CONCLUSION The DPV registry enabled us to precisely characterize phenotype and treatment in these two rare MODY types. Although phenotype of HNF4A- and HNF1B-MODY showed distinct differences from those of T1D and T2D, 38% of patients were initially misclassified as having T1D or T2D.
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Affiliation(s)
- Katharina Warncke
- Department of Pediatrics, Klinikum Rechts der Isar, Technische Universität München, Munich, Germany
| | - Sebastian Kummer
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital Medical Faculty, Düsseldorf, Germany
| | - Klemens Raile
- Department of Paediatric Endocrinology and Diabetology, Charité, Berlin, Germany
| | | | - Joachim Woelfle
- Pediatric Endocrinology Division, Children's Hospital, University of Bonn, Bonn, Germany
| | - Elisabeth Steichen
- Department of Pediatrics, Medical University of Innsbruck, Innsbruck, Austria
| | - Nicole Prinz
- Institute of Epidemiology and Medical Biometry, Central Institute for Biomedical Technology, University of Ulm, Ulm, Germany
- German Center for Diabetes Research, Munich-Neuherberg, Germany
| | - Reinhard W Holl
- Institute of Epidemiology and Medical Biometry, Central Institute for Biomedical Technology, University of Ulm, Ulm, Germany
- German Center for Diabetes Research, Munich-Neuherberg, Germany
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Johnson SR, Ellis JJ, Leo PJ, Anderson LK, Ganti U, Harris JE, Curran JA, McInerney-Leo AM, Paramalingam N, Song X, Conwell LS, Harris M, Jones TW, Brown MA, Davis EA, Duncan EL. Comprehensive genetic screening: The prevalence of maturity-onset diabetes of the young gene variants in a population-based childhood diabetes cohort. Pediatr Diabetes 2019; 20:57-64. [PMID: 30191644 DOI: 10.1111/pedi.12766] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2018] [Revised: 07/05/2018] [Accepted: 08/12/2018] [Indexed: 01/08/2023] Open
Abstract
BACKGROUND Maturity-onset diabetes of the young (MODY) is caused by autosomal dominant mutations in one of 13 confirmed genes. Estimates of MODY prevalence vary widely, as genetic screening is usually restricted based on clinical features, even in population studies. We aimed to determine prevalence of MODY variants in a large and unselected pediatric diabetes cohort. METHODS MODY variants were assessed using massively parallel sequencing in the population-based diabetes cohort (n = 1363) of the sole tertiary pediatric diabetes service for Western Australia (population 2.6 million). All individuals were screened, irrespective of clinical features. MODY variants were also assessed in a control cohort (n = 993). RESULTS DNA and signed consent were available for 821 children. Seventeen children had pathogenic/likely pathogenic variants in MODY genes, two diagnosed with type 2 diabetes, four diagnosed with antibody-negative type 1 diabetes (T1DM), three diagnosed with antibody-positive T1DM, and eight previously diagnosed with MODY. Prevalence of MODY variants in the sequenced cohort was 2.1%, compared to 0.3% of controls. CONCLUSIONS This is the first comprehensive study of MODY variants in an unselected population-based pediatric diabetes cohort. The observed prevalence, increasing access to rapid and affordable genetic screening, and significant clinical implications suggest that genetic screening for MODY could be considered for all children with diabetes, irrespective of other clinical features.
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Affiliation(s)
- Stephanie R Johnson
- Department of Endocrinology and Diabetes, Lady Cilento Children's Hospital, South Brisbane, Queensland, Australia.,Institute of Health and Biomedical Innovation, Faculty of Health, Queensland University of Technology (QUT), Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | - Jonathan J Ellis
- Institute of Health and Biomedical Innovation, Faculty of Health, Queensland University of Technology (QUT), Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | - Paul J Leo
- Institute of Health and Biomedical Innovation, Faculty of Health, Queensland University of Technology (QUT), Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | - Lisa K Anderson
- Institute of Health and Biomedical Innovation, Faculty of Health, Queensland University of Technology (QUT), Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | - Uma Ganti
- Department of Endocrinology and Diabetes, Perth Children's Hospital, Perth, Western Australia, Australia.,Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia
| | - Jessica E Harris
- Institute of Health and Biomedical Innovation, Faculty of Health, Queensland University of Technology (QUT), Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | - Jacqueline A Curran
- Department of Endocrinology and Diabetes, Perth Children's Hospital, Perth, Western Australia, Australia.,Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia
| | - Aideen M McInerney-Leo
- Institute of Health and Biomedical Innovation, Faculty of Health, Queensland University of Technology (QUT), Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.,University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | - Nirubasini Paramalingam
- Department of Endocrinology and Diabetes, Perth Children's Hospital, Perth, Western Australia, Australia.,Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia
| | - Xiaoxia Song
- Institute of Health and Biomedical Innovation, Faculty of Health, Queensland University of Technology (QUT), Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | - Louise S Conwell
- Department of Endocrinology and Diabetes, Lady Cilento Children's Hospital, South Brisbane, Queensland, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Mark Harris
- Department of Endocrinology and Diabetes, Lady Cilento Children's Hospital, South Brisbane, Queensland, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,University of Queensland Diamantina Institute, Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | - Timothy W Jones
- Department of Endocrinology and Diabetes, Perth Children's Hospital, Perth, Western Australia, Australia.,Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia.,School of Medicine, University of Western Australia, Perth, Western Australia, Australia
| | - Matthew A Brown
- Institute of Health and Biomedical Innovation, Faculty of Health, Queensland University of Technology (QUT), Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia
| | - Elizabeth A Davis
- Department of Endocrinology and Diabetes, Perth Children's Hospital, Perth, Western Australia, Australia.,Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia.,School of Medicine, University of Western Australia, Perth, Western Australia, Australia
| | - Emma L Duncan
- Institute of Health and Biomedical Innovation, Faculty of Health, Queensland University of Technology (QUT), Translational Research Institute, Princess Alexandra Hospital, Brisbane, Queensland, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia.,Department of Endocrinology and Diabetes, Royal Brisbane and Women's Hospital, Brisbane, Queensland, Australia
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Abstract
In addition to the common types of diabetes mellitus, two major monogenic diabetes forms exist. Maturity-onset diabetes of the young (MODY) represents a heterogenous group of monogenic, autosomal dominant diseases. MODY accounts for 1-2% of all diabetes cases, and it is not just underdiagnosed but often misdiagnosed to type 1 or type 2 diabetes. More than a dozen MODY genes have been identified to date, and their molecular classification is of great importance in the correct treatment decision and in the judgment of the prognosis. The most prevalent subtypes are HNF1A, GCK, and HNF4A. Genetic testing for MODY has changed recently due to the technological advancements, as contrary to the sequential testing performed in the past, nowadays all MODY genes can be tested simultaneously by next-generation sequencing. The other major group of monogenic diabetes is neonatal diabetes mellitus which can be transient or permanent, and often the diabetes is a part of a syndrome. It is a severe monogenic disease appearing in the first 6 months of life. The hyperglycemia usually requires insulin. There are two forms, permanent neonatal diabetes mellitus (PNDM) and transient neonatal diabetes mellitus (TNDM). In TNDM, the diabetes usually reverts within several months but might relapse later in life. The incidence of NDM is 1:100,000-1:400,000 live births, and PNDM accounts for half of the cases. Most commonly, neonatal diabetes is caused by mutations in KCNJ11 and ABCC8 genes encoding the ATP-dependent potassium channel of the β cell. Neonatal diabetes has experienced a quick and successful transition into the clinical practice since the discovery of the molecular background. In case of both genetic diabetes groups, recent guidelines recommend genetic testing.
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Affiliation(s)
- Zsolt Gaál
- 4th Department of Medicine, Jósa András Teaching Hospital, Nyíregyháza, Hungary
| | - István Balogh
- Division of Clinical Genetics, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.
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Shepherd MH, Shields BM, Hudson M, Pearson ER, Hyde C, Ellard S, Hattersley AT, Patel KA. 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 2018; 61:2520-2527. [PMID: 30229274 PMCID: PMC6223847 DOI: 10.1007/s00125-018-4728-6] [Citation(s) in RCA: 67] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Accepted: 07/31/2018] [Indexed: 12/16/2022]
Abstract
AIMS/HYPOTHESIS Treatment change following a genetic diagnosis of MODY is frequently indicated, but little is known about the factors predicting future treatment success. We therefore conducted the first prospective study to determine the impact of a genetic diagnosis on individuals with GCK-, HNF1A- or HNF4A-MODY in the UK, and to identify clinical characteristics predicting treatment success (i.e. HbA1c ≤58 mmol/mol [≤7.5%]) with the recommended treatment at 2 years. METHODS This was an observational, prospective, non-selective study of individuals referred to the Exeter Molecular Genetic Laboratory for genetic testing from December 2010 to December 2012. Individuals from the UK with GCK- or HNF1A/HNF4A-MODY who were not on recommended treatment at the time of genetic diagnosis, and who were diagnosed below the age of 30 years and were currently aged less than 50 years, were eligible to participate. RESULTS A total of 44 of 58 individuals (75.9%) changed treatment following their genetic diagnosis. Eight individuals diagnosed with GCK-MODY stopped all diabetes medication without experiencing any change in HbA1c (49.5 mmol/mol [6.6%] both before the genetic diagnosis and at a median of 1.25 years' follow-up without treatment, p = 0.88). A total of 36 of 49 individuals (73.5%) diagnosed with HNF1A/HNF4A-MODY changed treatment; however, of the 21 of these individuals who were being managed with diet or sulfonylurea alone at 2 years, only 13 (36.1% of the population that changed treatment) had an HbA1c ≤58 mmol/mol (≤7.5%). These individuals had a shorter diabetes duration (median 4.6 vs 18.1 years), lower HbA1c (58 vs 73 mmol/mol [7.5% vs 8.8%]) and lower BMI (median 24.2 vs 26.0 kg/m2) at the time of genetic diagnosis, compared with individuals (n = 23/36) with an HbA1c >58 mmol/mol (>7.5%) (or <58 mmol/mol [<7.5%] on additional treatment) at the 2 year follow-up. Overall, 64% (7/11) individuals with a diabetes duration of ≤11 years and an HbA1c of ≤69 mmol/mol (≤8.5%) at time of the genetic test achieved good glycaemic control (HbA1c ≤58 mmol/mol [≤7.5%]) with diet or sulfonylurea alone at 2 years, compared with no participants with a diabetes duration of >11 years and an HbA1c of >69 mmol/mol (>8.5%) at the time of genetic diagnosis. CONCLUSIONS/INTERPRETATION In participants with GCK-MODY, treatment cessation was universally successful, with no change in HbA1c at follow-up. In those with HNF1A/HNF4A-MODY, a shorter diabetes duration, lower HbA1c and lower BMI at genetic diagnosis predicted successful treatment with sulfonylurea/diet alone, supporting the need for early genetic diagnosis and treatment change. Our study suggests that, in individuals with HNF1A/HNF4A-MODY with a longer duration of diabetes (>11 years) at time of genetic test, rather than ceasing current treatment, a sulfonylurea should be added to existing therapy, particularly in those who are overweight or obese and have a high HbA1c.
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Affiliation(s)
- Maggie H Shepherd
- NIHR Exeter Clinical Research Facility, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD, Barrack Road, Exeter, EX2 5DW, UK.
| | - Beverley M Shields
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD, Barrack Road, Exeter, EX2 5DW, UK
| | - Michelle Hudson
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD, Barrack Road, Exeter, EX2 5DW, UK
| | - Ewan R Pearson
- Division of Population Health and Genomics, School of Medicine, University of Dundee, Dundee, UK
| | - Christopher Hyde
- Exeter Test Group, Institute of Health Research, University of Exeter Medical School, University of Exeter, Exeter, UK
| | - Sian Ellard
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD, Barrack Road, Exeter, EX2 5DW, UK
- Department of Molecular Genetics, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK
| | - Andrew T Hattersley
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD, Barrack Road, Exeter, EX2 5DW, UK
| | - Kashyap A Patel
- Institute of Biomedical and Clinical Science, University of Exeter Medical School, RILD, Barrack Road, Exeter, EX2 5DW, UK
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50
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Tapia G, Størdal K, Mårild K, Kahrs CR, Skrivarhaug T, Njølstad PR, Joner G, Stene LC. Antibiotics, acetaminophen and infections during prenatal and early life in relation to type 1 diabetes. Int J Epidemiol 2018; 47:1538-1548. [PMID: 29868838 PMCID: PMC6208272 DOI: 10.1093/ije/dyy092] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 04/24/2018] [Accepted: 05/09/2018] [Indexed: 02/06/2023] Open
Abstract
Background Infections in early life have been linked to type 1 diabetes (T1D) risk, but no previous study has comprehensively analysed exposure to antibiotics, acetaminophen and infections during pregnancy and early childhood in relation to offspring risk of T1D. Methods Participants in the Norwegian Mother and Child Cohort Study (n = 114 215 children, of whom 403 children were diagnosed with T1D) reported infections and medication use through repeated questionnaires from pregnancy until the children were 18 months old. Adjusted hazard ratios (aHR) for offspring T1D were estimated through Cox regression adjusted for child's sex, maternal age and parity, maternal T1D, smoking in pregnancy, education level, pre-pregnancy body mass index (BMI) and birthweight. Antibiotic use was also analysed in a population-based register cohort of 541 036 children of whom 836 developed T1D. Results Hospitalization for gastroenteritis during the first 18 months of life was associated with increased risk (aHR 2.27, 95% CI 1.21 - 4.29, P = 0.01) of T1D. Childhood infections not requiring hospitalization, or any kind of maternal infection during pregnancy, did not predict offspring risk of T1D. Antibiotic or acetaminophen use in pregnancy, or child`s use in early childhood, was not associated with risk of T1D. Conclusions Our study, which is population-based and the largest of its kind, did not find support for general early life infections, infection frequency or use of antibiotics or acetaminophen to play a major role in childhood T1D. Hospital admission for gastroenteritis was associated with T1D risk, but must be interpreted cautiously due to scarcity of cases.
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Affiliation(s)
- German Tapia
- Department of Child Health, Norwegian Institute of Public Health, Oslo, Norway
| | - Ketil Størdal
- Department of Child Health, Norwegian Institute of Public Health, Oslo, Norway
- Pediatric Department, Østfold Hospital Trust, Grålum, Norway
| | - Karl Mårild
- Department of Child Health, Norwegian Institute of Public Health, Oslo, Norway
- Barbara Davis Center, University of Colorado, Aurora, CO, USA
| | | | - Torild Skrivarhaug
- Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Pål R Njølstad
- KG Jebsen Center for Diabetes Research, Department of Clinical Science, University of Bergen, Bergen, Norway
- Department of Pediatrics and Adolescent Medicine, Haukeland University Hospital, Bergen, Norway
| | - Geir Joner
- Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Lars C Stene
- Department of Child Health, Norwegian Institute of Public Health, Oslo, Norway
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