Systematic Assessment of Etiology in Adults With a Clinical Diagnosis of Young-Onset Type 2 Diabetes Is a Successful Strategy for Identifying Maturity-Onset Diabetes of the Young

OBJECTIVE Misdiagnosis of maturity-onset diabetes of the young (MODY) remains widespread, despite the benefits of optimized management. This cross-sectional study examined diagnostic misclassification of MODY in subjects with clinically labeled young adult-onset type 1 and type 2 diabetes by extending genetic testing beyond current guidelines. RESEARCH DESIGN AND METHODS Individuals were selected for diagnostic sequencing if they displayed features atypical for their diagnostic label. From 247 case subjects with clinically labeled type 1 diabetes, we sequenced hepatocyte nuclear factor 1 α (HNF1A) and hepatocyte nuclear factor 4 α (HNF4A) in 20 with residual β-cell function ≥ 3 years from diagnosis (random or glucagon-stimulated C-peptide ≥ 0.2 nmol/L). From 322 with clinically labeled type 2 diabetes, we sequenced HNF1A and HNF4A in 80 with diabetes diagnosed ≤ 30 years and/or diabetes diagnosed ≤ 45 years without metabolic syndrome. We also sequenced the glucokinase (GCK) in 40 subjects with mild fasting hyperglycemia. RESULTS In the type 1 diabetic group, two HNF1A mutations were found (0.8% prevalence). In type 2 diabetic subjects, 10 HNF1A, two HNF4A, and one GCK mutation were identified (4.0%). Only 47% of MODY case subjects identified met current guidelines for diagnostic sequencing. Follow-up revealed a further 12 mutation carriers among relatives. Twenty-seven percent of newly identified MODY subjects changed treatment, all with improved glycemic control (HbA(1c) 8.8 vs. 7.3% at 3 months; P = 0.02). CONCLUSIONS The systematic use of widened diagnostic testing criteria doubled the numbers of MODY case subjects identified compared with current clinical practice. The yield was greatest in young adult-onset type 2 diabetes. We recommend that all patients diagnosed before age 30 and with presence of C-peptide at 3 years' duration are considered for molecular diagnostic analysis.