Population Prevalence, Penetrance, and Mortality for Genetically Confirmed MODY

CONTEXT: Diagnosing maturity-onset diabetes of the young (MODY) is clinically important for treatment and prognosis. However, phenotype-based studies of MODY are prone to ascertainment bias, limiting accurate estimates of its population prevalence and phenotypic spectrum. OBJECTIVE: To apply a genotype-first approach to determine the population prevalence, penetrance, and all-cause mortality associated with MODY. METHODS: We analyzed exome sequencing and clinical data from 454 275 UK Biobank participants to identify pathogenic variants in 10 established MODY genes. We assessed variant prevalence, age-dependent diabetes penetrance, and all-cause mortality by genetic etiology over a mean follow-up of 13.4 years. RESULTS: Pathogenic MODY variants were present in 1 in 1052 individuals and accounted for 1.48% of diabetes cases diagnosed before age 40. GCK variants were the most frequent (1 in 2787), demonstrating high penetrance (mean HbA1c 8.8 mmol/mol higher; 94.5% with prediabetes or diabetes) but no significant association with all-cause mortality (P = .09). Variants in other MODY genes showed lower penetrance, with 12% of carriers developing diabetes by age 40 and 31.6% by age 60 and showed no increase in all-cause mortality (P = .89). Penetrance varied by genetic etiology, with HNF1A showing the highest penetrance and PDX1, NEUROD1, and RFX6 the lowest. Parental history of diabetes and polygenic risk for type 2 diabetes were important modifiers of penetrance (hazard ratios 2.54 and 1.52, respectively; P < 3.9 × 10-3). CONCLUSION: This large-scale genotype-first study provides novel insights into MODY in the population. These findings have broad implications for genetic counseling, personalized treatment strategies, and healthcare resource allocation.