Population Prevalence, Penetrance, and Mortality for Genetically Confirmed MODY

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.

To apply a genotype-first approach to determine the population prevalence, penetrance, and all-cause mortality associated with MODY.

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.

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).

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.