| Title: | Population Prevalence, Penetrance, and Mortality for Genetically Confirmed MODY |
| Journal: | The Journal of Clinical Endocrinology & Metabolism |
| Published: | 1 Nov 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41175096/ |
| DOI: | https://doi.org/10.1210/clinem/dgaf599 |
| URL: | https://academic.oup.com/jcem/advance-article-pdf/doi/10.1210/clinem/dgaf599/65052341/dgaf599.pdf |
Publication 19087
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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.</p>
OBJECTIVE: To apply a genotype-first approach to determine the population prevalence, penetrance, and all-cause mortality associated with MODY.</p>
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.</p>
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).</p>
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.</p>
15 Keywords
- Adult
- Aged
- Diabetes Mellitus, Type 2
- Exome Sequencing
- Female
- Follow-Up Studies
- Genetic Predisposition to Disease
- Genotype
- Humans
- Male
- Middle Aged
- Penetrance
- Prevalence
- United Kingdom
- Young Adult
8 Authors
- Luke N Sharp
- Kevin Colclough
- Jacques Murray Leech
- Stuart J Cannon
- Thomas W Laver
- Andrew T Hattersley
- Michael N Weedon
- Kashyap A Patel
1 Application
| Application ID | Title |
|---|---|
| 103356 | Understanding the role of rare and common genetic variation in human phenotypes |
Enabling scientific discoveries that improve human health