Monogenic Diabetes in Youth With Presumed Type 2 Diabetes: Results From the Progress in Diabetes Genetics in Youth (ProDiGY) Collaboration

<p>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 multi-ethnic youth under age 20 years with a clinical diagnosis of type 2 diabetes.</p> <p> </p> <p>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.</p> <p> </p> <p>Results: 93 of 3,333 participants (2.8%) carried an LP/P variant in <i>HNF4A </i>(16 participants)<i>, GCK </i>(23)<i>, HNF1A </i>(44), <i>PDX1</i> (5), <i>INS</i> (4), and <i>CEL</i> (1). Compared with those with no LP/P variants, youth with MODY had a younger age at diagnosis (12.9 ± 2.5 <i>vs</i> 13.6 ± 2.3 years, <i>P</i>=0.002) and lower fasting C-peptide levels (3.0 ± 1.7 <i>vs</i> 4.7 ± 3.5 ng/mL, <i>P</i><0.0001). Youth with MODY were less likely to have hypertension (6.9% <i>vs</i> 19.5%, <i>P</i>=0.007) and had higher HDL cholesterol (43.8 <i>vs</i> 39.7 mg/dL, <i>P=</i>0.006). </p> <p> </p> 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 to select individuals for genetic testing.