Monogenic diabetes, including maturity-onset diabetes of the young (MODY), is frequently misdiagnosed as type 1 or type 2 diabetes. Correct diagnosis can result in a change in clinical treatment and impacts prediction of complications and familial risk. Clinical algorithms can select individuals for genetic testing; however, up to half of youth with MODY do not meet clinical criteria. Other barriers also limit access to genetic testing.

To assess the prevalence of MODY in youth with a clinical diagnosis of type 2 diabetes, we evaluated whole-exome sequence data from ProDiGY, a collaboration of the TODAY, SEARCH for Diabetes in Youth, and T2D-GENES studies. Focusing on 14 genes previously identified as causal for MODY (HNF4A, GCK, HNF1A, PDX1, HNF1B, NEUROD1, KLF11, CEL, PAX4, INS, BLK, KCNJ11, ABCC8, and APPL1) we considered patients to have MODY if they carried one or more variants classified as likely pathogenic (LP) or pathogenic (P) according to current guidelines. We found 77 of 3650 patients carried an LP/P variant in HNF4A (14 individuals), GCK (22), HNF1A (32), PDX1 (4), INS (3), and PAX4 (2). Compared to those with no LP/P variants, youth with MODY had a younger age at diagnosis (12.9 ± 0.3 vs. 13.6 ± 0.1, P=0.01) and lower fasting C-peptide levels (3.0 ± 0.2 vs. 4.5 ± 0.1, P=0.0001), although for both measures, the range of values overlapped between the two groups. Youth with MODY were less likely to have hypertension (6.9% vs. 18.2%, P=0.03) and less likely to be on insulin (32.0% vs. 51.1%, P=0.001). Parental history of diabetes was not significantly different. MODY was found in all race/ethnic groups.

Using a comprehensive set of MODY genes, we identified MODY in 2% of youth with clinically diagnosed type 2 diabetes; in 88% (n=68) the specific diagnosis would direct management. While these individuals differed significantly on several clinical characteristics, no criterion reliably separated the two groups. Further study is needed to find ideal criteria to select individuals for genetic testing.


J. Todd: None. J.W. Kleinberger: None. S. Srinivasan: None. S.E. Tollefsen: None. L.L. Levitsky: Consultant; Self; Eli Lilly and Company. L.E.L. Katz: None. J.B. Tryggestad: None. F. Bacha: Research Support; Self; AstraZeneca, JAEB Center For Health Research, National Institutes of Health, Pediatric Diabetes Consortium. G. Imperatore: None. J.M. Lawrence: None. C. Pihoker: None. J. Divers: None. J. Flannick: None. D. Dabelea: None. J.C. Florez: Consultant; Self; Intarcia Therapeutics, Inc.. Consultant; Spouse/Partner; Santen. T.I. Pollin: Research Support; Self; Regeneron Pharmaceuticals, Inc..

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