| Title: |
Population Prevalence, Penetrance, and Mortality for Genetically Confirmed MODY. |
| Authors: |
Sharp, Luke N; Colclough, Kevin; Leech, Jacques Murray; Cannon, Stuart J; Laver, Thomas W; Hattersley, Andrew T; Weedon, Michael N; Patel, Kashyap A |
| Source: |
Journal of Clinical Endocrinology & Metabolism; May2026, Vol. 111 Issue 5, pe1388-e1395, 8p |
| Subject Terms: |
MATURITY onset diabetes of the young; DNA sequencing; MORTALITY; GENETIC epidemiology; TYPE 2 diabetes; GENE expression; INDIVIDUALIZED medicine; BIOBANKS |
| Abstract: |
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. [ABSTRACT FROM AUTHOR] |
| : |
Copyright of Journal of Clinical Endocrinology & Metabolism is the property of Oxford University Press / USA and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) |
| Database: |
Complementary Index |