Monogenic diabetes in youth with presumed type 2 diabetes: Results from the Progress in Diabetes Genetics in Youth (ProDiGY) collaboration

Authors: TODD, JENNIFER - University Of Vermont; KLEINBERGER, JEFFREY - University Of Maryland School Of Medicine; ZHANG, HAICHEN - University Of Maryland School Of Medicine; SRINIVASAN, SHYLAJA - University Of California; TOLLEFSEN, SHERIDA - St Louis University; LEVITSKY, LYNNE - Massachusetts General Hospital; LEVITT KATZ, LORRAINE - University Of Pennsylvania; TRYGGESTAD, JEANIE - University Of Oklahoma Health Sciences Center; BACHA, FIDA - Children'S Nutrition Research Center (CNRC); IMPERATORE, GIUSEPPINA - Centers For Disease Control And Prevention (CDC) - United States; LAWRENCE, JEAN - Kaiser Permanente; PIHOKER, CATHERINE - University Of Washington; DIVERS, JASMIN - New York University; FLANNICK, JASON - Boston Children'S Hospital; DABELEA, DANA - University Of Colorado; FLOREZ, JOSE - Massachusetts General Hospital; POLLIN, TONI - University Of Maryland School Of Medicine

Submitted to: Diabetes Care
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/1/2021
Publication Date: 8/6/2021
Citation: Todd, J.N., Kleinberger, J.W., Zhang, H., Srinivasan, S., Tollefsen, S.E., Levitsky, L.L., Levitt Katz, L.E., Tryggestad, J.B., Bacha, F., Imperatore, G., Lawrence, J.M., Pihoker, C., Divers, J., Flannick, J., Dabelea, D., Florez, J.C., Pollin, T.I. 2021. Monogenic diabetes in youth with presumed type 2 diabetes: Results from the Progress in Diabetes Genetics in Youth (ProDiGY) collaboration. Diabetes Care. 44(10):2312-2319. https://doi.org/10.2337/dc21-0491.
DOI: https://doi.org/10.2337/dc21-0491

Interpretive Summary: Maturity-onset diabetes of the young (MODY) is a form of diabetes related to specific genetic cause (monogenic). 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, researchers wanted to understand the prevalence of MODY in multiethnic youth under age 20 years with a clinical diagnosis of type 2 diabetes. Researchers evaluated genetic 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. Of 3,333 participants, 93 carried a gene variant that causes MODY. Compared with those with no variants, youth with MODY had a younger age at diagnosis and lower markers of insulin secretion. Youth with MODY were less likely to have hypertension and had higher HDL cholesterol. Therefore, a comprehensive genetic evaluation identified MODY in 2.8% of youth with clinically diagnosed type 2 diabetes. In 89% of those, the specific diagnosis would have changed clinical management. On the other hand, clinical measures alone were not enough to reliably separate the two groups. New tools are needed to find ideal criteria for selection of individuals for genetic testing.

Technical Abstract: 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. 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. 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. 39.7mg/dL, P = 0.006). 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.