Evidence map›Paper›PMID 41772234›Full record

ArticleDiabetologia2026

Systematic analysis of loss-of-function variants across MODY genes demonstrates gene-specific effects and expands the spectrum of INS variants causing MODY.

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 and 2 more

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Article in Diabetologia, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

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1citing papers in PubMed
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1 · What the graph read from it

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2 · The registry

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3 · Its place in the literature

Who cites it

1 citing paper in PubMed.

  1. Article
4 · The record

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5 · Who and what money

Authors and funding

12 authors.

Thomas W LaverDepartment of Clinical and Biomedical Science, University of Exeter, Exeter, UK.
Aparajita SriramDepartment of Clinical and Biomedical Science, University of Exeter, Exeter, UK.
Matthew N WakelingDepartment of Clinical and Biomedical Science, University of Exeter, Exeter, UK.
Zeynep ŞiklarAnkara University Faculty of Medicine, Department of Paediatric Endocrinology, Ankara, Turkey.
Farah KobaisiUniversité Paris Cité, Institut Cochin, CNRS, Inserm, Paris, France.
Oguzhan KalyonDepartment of Clinical and Biomedical Science, University of Exeter, Exeter, UK.
Andrew T HattersleyDepartment of Clinical and Biomedical Science, University of Exeter, Exeter, UK.
Michael N WeedonDepartment of Clinical and Biomedical Science, University of Exeter, Exeter, UK.
Sarah E FlanaganDepartment of Clinical and Biomedical Science, University of Exeter, Exeter, UK.
Elisa De FrancoDepartment of Clinical and Biomedical Science, University of Exeter, Exeter, UK.
Kevin ColcloughRoyal Devon and Exeter NHS Foundation Trust, Exeter, UK.
Kashyap A PatelDepartment of Clinical and Biomedical Science, University of Exeter, Exeter, UK. k.a.patel@exeter.ac.uk.

Funding

No grant is acknowledged in the PubMed record.

6 · The paper itself

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 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.

Indexed as

Diabetes Mellitus, Type 2InsulinLoss of Function MutationAdultFemaleGene FrequencyGenetic Predisposition to DiseaseHumansMaleNonsense Mediated mRNA DecayRegulatory Factor X Transcription FactorsInsulinRegulatory Factor X Transcription FactorsRfx6 protein, humanGene-burden testingINSLoss-of-function variantsMODYMODY gene pathogenicityNonsense-mediated decay

Identifiers

PMID41772234
PMCPMC13109276

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.