MODY Is Prevalent in Later-Onset Diabetes and Has Potential for Targeted Therapy but Is Challenging to Identify

Maturity onset diabetes of the young (MODY) can present after the age of 40 years, but its prevalence and clinical characteristics, and the utility of simple clinical features for selecting cases in this age group remain poorly defined. We analyzed whole-exome and clinical data from 51,619 individuals with diabetes diagnosed after age 40 years from one U.K. and one U.S. cohort. The prevalence of MODY due to a pathogenic variant in the 10 mostcommon MODY genes was 1 in 191 (0.52%) in the U.K. cohort and 1 in 633 (0.16%) in the U.S. cohort. For subtypes with treatment implications (i.e., GCK, HNF1A, HNF4A, ABCC8, KCNJ11), prevalence was 1 in 234 and 1 in 935 in the U.K. and U.S. cohorts, respectively. GCK-MODY was most common, followed by HNF4A and the lower-penetrance RFX6-MODY. Clinical features of MODY largely overlapped with non-MODY diabetes either treated with insulin from diagnosis or not. Only BMI, HbA1c and HDL values were statistically different between patients with MODY and those with non-MODY diabetes in both cohorts (P < 0.0018 for all). Applying strict clinical criteria (i.e., BMI <25, noninsulin treated, and parent with diabetes) only increased the MODY diagnosis to 2.64% and 0.87% in the respective cohorts but missed >86% of cases. MODY is prevalent in later-onset diabetes and has potential for targeted therapy but is challenging to identify. Article Highlights Maturity onset diabetes of the young (MODY) can present later in life, and diagnosis can enable precision treatment. However, individuals with later-onset diabetes are rarely tested. How common is MODY in people diagnosed with diabetes after age 40 years? Can they be identified clinically? MODY affects 1 in 191–633 individuals with diabetes onset after 40 years, but clinical features alone cannot reliably identify them. MODY is relatively common in later-onset diabetes but difficult to detect clinically, limiting routine genetic testing in this group.