| Title: | Systematic analysis of loss-of-function variants across MODY genes demonstrates gene-specific effects and expands the spectrum of INS variants causing MODY |
| Journal: | Diabetologia |
| Published: | 3 Mar 2026 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/41772234/ |
| DOI: | https://doi.org/10.1007/s00125-026-06685-7 |
Publication 17507
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Abstract
Aims/hypothesisAccurate interpretation of loss-of-function (LOF) variants in MODY genes is essential for diagnosis but remains challenging, particularly for variants that are predicted to escape nonsense-mediated decay (NMD). We aimed to systematically evaluate the pathogenicity of LOF variants, stratified by NMD-triggering and NMD-escape status, across all known MODY genes.MethodsWe analysed ultra-rare LOF variants (minor allele frequency <1 in 10,000) in 5171 individuals of European ancestry with suspected MODY, compared with 155,501 population-based control individuals from UK Biobank. LOF variants in ABCC8, GCK, HNF1A, HNF4A, HNF1B, INS, KCNJ11, NEUROD1, PDX1 and RFX6 were classified as NMD-triggering or NMD-escape. We tested for gene-level enrichment in cases vs controls. For novel associations, we performed replication in additional MODY patients, assessed familial co-segregation, and undertook in silico protein modelling.ResultsLOF variants were significantly enriched in all MODY genes except ABCC8 and KCNJ11. Both NMD-triggering and NMD-escape variants were enriched in GCK, HNF1A and HNF4A, consistent with haploinsufficiency (all p<10−3). HNF1B and RFX6 showed enrichment only for NMD-triggering variants, while NEUROD1 and PDX1 were enriched only for NMD-escape variants. A novel finding was the significant enrichment of only NMD-escape LOF variants in INS (OR=181, p<10−5). Including replication in additional MODY patients, we identified eight families with 17 affected individuals carrying INS variants. These variants co-segregated with diabetes (logarithm of the odds score=3), included one de novo case, and were absent from >800,000 population control individuals. Individuals presented with diabetes at a median age of 19 years, had median BMI of 22.9 kg/m2, were negative for islet autoantibodies, and had low type 1 diabetes genetic risk scores. Compared with INS missense MODY, diagnosis occurred approximately 10 years later in individuals with NMD-escape LOF variants. Protein modelling suggested that INS NMD-escape variants produce aberrant proinsulin molecules with unpaired B-chain cysteines, leading to milder misfolding.Conclusions/interpretationThe pathogenicity of LOF variants in MODY genes depends on gene context and NMD status. Heterozygous NMD-escape LOF variants in INS are a novel cause of MODY. These findings provide systematic gene-level evidence to inform variant interpretation guidelines and improve the accuracy of MODY diagnosis in clinical practice.Graphical Abstract</p>
12 Authors
- Thomas W. Laver
- Aparajita Sriram
- Matthew N. Wakeling
- Zeynep Şiklar
- Farah Kobaisi
- Oguzhan Kalyon
- Andrew T. Hattersley
- Michael N. Weedon
- Sarah E. Flanagan
- Elisa De Franco
- Kevin Colclough
- Kashyap A. Patel
1 Application
| Application ID | Title |
|---|---|
| 9072 | The Genetics of anthropometric traits ? Height, weight, BMI and waist circumference |
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