Monogenic Diabetes in Youth With Presumed Type 2 Diabetes: Results From the Progress in Diabetes Genetics in Youth (ProDiGY) Collaboration
Year: 2021
Type: article
Study design: Observational Study
Abstract: OBJECTIVE Maturity-onset diabetes of the young (MODY) is frequently misdiagnosed as type 1 or type 2 diabetes. Correct diagnosis may result in a change in clinical treatment and impacts prediction of complications and familial risk. In this study, we aimed to assess the prevalence of MODY in multiethnic youth under age 20 years with a clinical diagnosis of type 2 diabetes. RESEARCH DESIGN AND METHODS We evaluated whole-exome sequence data of youth with a clinical diagnosis of type 2 diabetes. We considered participants to have MODY if they carried a MODY gene variant classified as likely pathogenic (LP) or pathogenic (P) according to current guidelines. RESULTS Of 3,333 participants, 93 (2.8%) carried an LP/P variant in HNF4A (16 participants), GCK (23), HNF1A (44), PDX1 (5), INS (4), and CEL (1). Compared with those with no LP/P variants, youth with MODY had a younger age at diagnosis (12.9 ± 2.5 vs. 13.6 ± 2.3 years, P = 0.002) and lower fasting C-peptide levels (3.0 ± 1.7 vs. 4.7 ± 3.5 ng/mL, P < 0.0001). Youth with MODY were less likely to have hypertension (6.9% vs. 19.5%, P = 0.007) and had higher HDL cholesterol (43.8 vs. 39.7 mg/dL, P = 0.006). CONCLUSIONS By comprehensively sequencing the coding regions of all MODY genes, we identified MODY in 2.8% of youth with clinically diagnosed type 2 diabetes; importantly, in 89% (n = 83) the specific diagnosis would have changed clinical management. No clinical criterion reliably separated the two groups. New tools are needed to find ideal criteria for selection of individuals for genetic testing.
Source: Diabetes Care
DOI: 10.2337/dc21-0491
Authors: Jennifer N. Todd, Jeffrey W. Kleinberger, Haichen Zhang, Shylaja Srinivasan, Sherida E. Tollefsen, Lynne L. Levitsky, Lorraine E. Levitt Katz, Jeanie B. Tryggestad, Fida Bacha, Giuseppina Imperatore, Jean M. Lawrence, Catherine Pihoker, Jasmin Divers, Jason Flannick, Dana Dabelea, Jose C. Florez, Toni I. Pollin
Institutions: Broad Institute, University of Vermont, Boston Children's Hospital, Massachusetts General Hospital, University of Maryland, Baltimore, University of California, San Francisco, Saint Louis University, Harvard University, Children's Hospital of Philadelphia, University of Pennsylvania, University of Oklahoma Health Sciences Center, Baylor College of Medicine, Children's Nutrition Research Center at Baylor College of Medicine, Centers for Disease Control and Prevention, Kaiser Permanente, University of Washington, NYU Langone Health, Colorado School of Public Health, University of Colorado Anschutz
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
Funders: Medical University of South Carolina, University of South Carolina, Ohio Department of Health, National Institutes of Health, National Heart, Lung, and Blood Institute, National Human Genome Research Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Center for Research Resources, National Center for Chronic Disease Prevention and Health Promotion, National Center for Advancing Translational Sciences
Awards: G1061576540, G1092462818, G1181497844, G1260873166, G130883262, G1389856746, Management of Pediatric Type 2 Diabetes Mellitus, Multi-Center Study of the Treatment of T2DM in Youth, G1535104519, G1536843008, G1609525565, G1650331929, G1711233980, G1789861183, G1824217007, G188987342, Colorado Clinical and Translational Science Institute (UL1), Large Scale Sequencing and Analysis of Genomes, G2078309758, G2091809135, G22646245, Case Western Reserve University/Cleveland Clinic CTSA (UL1), G2320993242, G2388603646, G2486139536, G2698360221, G2843424534, G2873368755, G2963698315, G299222429, G3064501752, G3071343646, G3314368649, G3437629819, Harvard Clinical and Translational Science Center (UL1), General Clinical Research Center, Institute of Translational Health Sciences, University of Pittsburgh Clinical and Translational Science Institute, South Carolina Clinical & Translational Research Institute (SCTR), Type 2 Diabetes in Youth: Beta Cell Preservation, G413336477, G426894015, G4614542344, Training Program in Pediatric Endocrinology, Treatment Alternatives in Pediatric Type 2 Diabetes, G475936976, G486112768, G4976965329, TODAY2 Phase 2 (T2P2): Long-Term Post-Intervention Follow-Up, G5212289133, G5304326513, Institutional Clinical and Translational Science Award, G554783770, G5724597403, G5754017158, General Clinical Research Center, General Clinical Research Center, CAREER DEVELOPMENT IN DIABETES RESEARCH FOR PEDIATRIC ENDOCRINOLOGISTS, G7270065953, G7729184613, Washington University Institute of Clinical and Translational Sciences (UL1), Yale University Clinical and Translational Science Award Program, G832786732, G874743574, G9000086239, Mentoring Investigators on the Clinical Translation of Cardiometabolic Genetic Discoveries, G903953877, Colorado Clinical and Translational Science Institute (UL1)
OpenAlex ID: W3192952735