{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,18]],"date-time":"2026-07-18T17:19:35Z","timestamp":1784395175975,"version":"3.55.0"},"reference-count":38,"publisher":"Springer Science and Business Media LLC","issue":"6","license":[{"start":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T00:00:00Z","timestamp":1772496000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100007885","name":"European Association for the Study of Diabetes","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007885","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Diabetologia"],"published-print":{"date-parts":[[2026,6]]},"abstract":"Abstract<\/jats:title>\n \n Aims\/hypothesis<\/jats:title>\n Accurate 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.<\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We 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\n ABCC8<\/jats:italic>\n ,\n GCK<\/jats:italic>\n ,\n HNF1A<\/jats:italic>\n ,\n HNF4A<\/jats:italic>\n ,\n HNF1B<\/jats:italic>\n ,\n INS<\/jats:italic>\n ,\n KCNJ11<\/jats:italic>\n ,\n NEUROD1<\/jats:italic>\n ,\n PDX1<\/jats:italic>\n and\n RFX6<\/jats:italic>\n 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.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n LOF variants were significantly enriched in all MODY genes except\n ABCC8<\/jats:italic>\n and\n KCNJ11<\/jats:italic>\n . Both NMD-triggering and NMD-escape variants were enriched in\n GCK<\/jats:italic>\n ,\n HNF1A<\/jats:italic>\n and\n HNF4A<\/jats:italic>\n , consistent with haploinsufficiency (all\n p<\/jats:italic>\n <10\n \u22123<\/jats:sup>\n ).\n HNF1B<\/jats:italic>\n and\n RFX6<\/jats:italic>\n showed enrichment only for NMD-triggering variants, while\n NEUROD1<\/jats:italic>\n and\n PDX1<\/jats:italic>\n were enriched only for NMD-escape variants. A novel finding was the significant enrichment of only NMD-escape LOF variants in\n INS<\/jats:italic>\n (OR=181,\n p<\/jats:italic>\n <10\n \u22125<\/jats:sup>\n ). Including replication in additional MODY patients, we identified eight families with 17 affected individuals carrying\n INS<\/jats:italic>\n 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\/m\n 2<\/jats:sup>\n , were negative for islet autoantibodies, and had low type 1 diabetes genetic risk scores. Compared with\n INS<\/jats:italic>\n missense MODY, diagnosis occurred approximately 10 years later in individuals with NMD-escape LOF variants. Protein modelling suggested that\n INS<\/jats:italic>\n NMD-escape variants produce aberrant proinsulin molecules with unpaired B-chain cysteines, leading to milder misfolding.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions\/interpretation<\/jats:title>\n \n The pathogenicity of LOF variants in MODY genes depends on gene context and NMD status. Heterozygous NMD-escape LOF variants in\n INS<\/jats:italic>\n 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.\n <\/jats:p>\n <\/jats:sec>\n \n Graphical Abstract<\/jats:title>\n <\/jats:sec>","DOI":"10.1007\/s00125-026-06685-7","type":"journal-article","created":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T02:22:32Z","timestamp":1772504552000},"page":"1569-1580","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Systematic analysis of loss-of-function variants across MODY genes demonstrates gene-specific effects and expands the spectrum of INS variants causing MODY"],"prefix":"10.1007","volume":"69","author":[{"given":"Thomas W.","family":"Laver","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aparajita","family":"Sriram","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew N.","family":"Wakeling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zeynep","family":"\u015eiklar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farah","family":"Kobaisi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oguzhan","family":"Kalyon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew T.","family":"Hattersley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael N.","family":"Weedon","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah E.","family":"Flanagan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"De Franco","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kevin","family":"Colclough","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kashyap A.","family":"Patel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,3]]},"reference":[{"key":"6685_CR1","doi-asserted-by":"publisher","first-page":"1645","DOI":"10.1038\/s41588-019-0517-5","volume":"51","author":"RGH Lindeboom","year":"2019","unstructured":"Lindeboom RGH, Vermeulen M, Lehner B, Supek F (2019) The impact of nonsense-mediated mRNA decay on genetic disease, gene editing and cancer immunotherapy. 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Diabetes 65(7):2094\u20132099. https:\/\/doi.org\/10.2337\/db15-1690","journal-title":"Diabetes"}],"container-title":["Diabetologia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00125-026-06685-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s00125-026-06685-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s00125-026-06685-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,24]],"date-time":"2026-04-24T11:07:41Z","timestamp":1777028861000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s00125-026-06685-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,3]]},"references-count":38,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,6]]}},"alternative-id":["6685"],"URL":"https:\/\/doi.org\/10.1007\/s00125-026-06685-7","relation":{},"ISSN":["0012-186X","1432-0428"],"issn-type":[{"value":"0012-186X","type":"print"},{"value":"1432-0428","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,3]]},"assertion":[{"value":"27 August 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 November 2025","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 March 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"This research was conducted using the UK Biobank Resource under UK Biobank project number 9072. The Wellcome Trust, MRC and NIHR had no role in the design and conduct of the study. collection, management, analysis or interpretation of the data, preparation, review or approval of the manuscript, or the decision to submit the manuscript for publication. The views expressed are those of the author(s) and not necessarily those of the Wellcome Trust, UK Department of Health, NHS or NIHR.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Acknowledgements"}},{"value":"Data on the MODY cohort are available through collaboration to experienced teams working on approved studies examining the mechanisms, diagnosis and treatment of diabetes and other beta cell disorders. Requests for collaboration will be considered by a steering committee following an application to the Genetic Beta Cell Research Bank (\n \n ). Contact by email should be directed to the corresponding author. Data from the UK Biobank are available to approved researchers (\n \n ). GnomAD data are publicly available (\n \n ).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Data availability"}},{"value":"This study was funded by the European Foundation for the Study of Diabetes. In addition, KAP is funded by the Wellcome Trust (219606\/Z\/19\/Z). TWL is supported by the Academy of Medical Sciences, the Wellcome Trust, the UK Government Department of Science Innovation and Technology, the British Heart Foundation and a Diabetes UK Springboard Award (SBF009\\1135). ATH is supported by a Wellcome Trust Senior Investigator award (WT098395\/Z\/12\/Z). FK is supported by Investissements d'Avenir (ANR-10-LABX-73-01) and the Dutch Diabetes Research Foundation (Stichting Diabetes Onderzoek Nederland [DON]). The work was also supported by the UK National Institute for Health Research (NIHR) Exeter Biomedical Research Centre, Exeter, UK, and the NIHR Exeter Clinical Research Facilities.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Funding"}},{"value":"The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Authors\u2019 relationships and activities"}},{"value":"TWL and AS are joint first authors. The study was conceptualised by KAP and TWL, with methodology design contributions from FK, MNWa, MNWe and OK. ATH, EDF, KC, SF, KAP and ZS recruited patients and contributed to the acquisition of the data. KAP, TWL, AS, FK and OK undertook data analysis. All authors contributed to the data interpretation. The original draft was prepared by AS, KAP and TWL, and AS, ATH, EDF, KC, KAP, MNWa, FK, MNWe, OK, SF, TWL and ZS critically reviewed, edited and provided crucial intellectual comments. Supervision was provided by KAP, and funding acquisition was undertaken by KAP, MNWe and TWL. All authors approved the final version for publication. KAP is the guarantor of this work, and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Contribution statement"}}]}}