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Aims/hypothesis <p>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.</p> Methods <p>We analysed ultra-rare LOF variants (minor allele frequency &lt;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 <i>ABCC8</i>, <i>GCK</i>, <i>HNF1A</i>, <i>HNF4A</i>, <i>HNF1B</i>, <i>INS</i>, <i>KCNJ11</i>, <i>NEUROD1</i>, <i>PDX1</i> and <i>RFX6</i> 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.</p> Results <p>LOF variants were significantly enriched in all MODY genes except <i>ABCC8</i> and <i>KCNJ11</i>. Both NMD-triggering and NMD-escape variants were enriched in <i>GCK</i>, <i>HNF1A</i> and <i>HNF4A</i>, consistent with haploinsufficiency (all <i>p</i>&lt;10<sup>−3</sup>). <i>HNF1B</i> and <i>RFX6</i> showed enrichment only for NMD-triggering variants, while <i>NEUROD1</i> and <i>PDX1</i> were enriched only for NMD-escape variants. A novel finding was the significant enrichment of only NMD-escape LOF variants in <i>INS</i> (OR=181, <i>p</i>&lt;10<sup>−5</sup>). Including replication in additional MODY patients, we identified eight families with 17 affected individuals carrying <i>INS</i> variants. These variants co-segregated with diabetes (logarithm of the odds score=3), included one de novo case, and were absent from &gt;800,000 population control individuals. Individuals presented with diabetes at a median age of 19 years, had median BMI of 22.9 kg/m<sup>2</sup>, were negative for islet autoantibodies, and had low type 1 diabetes genetic risk scores. Compared with <i>INS</i> missense MODY, diagnosis occurred approximately 10 years later in individuals with NMD-escape LOF variants. Protein modelling suggested that <i>INS</i> NMD-escape variants produce aberrant proinsulin molecules with unpaired B-chain cysteines, leading to milder misfolding.</p> Conclusions/interpretation <p>The pathogenicity of LOF variants in MODY genes depends on gene context and NMD status. Heterozygous NMD-escape LOF variants in <i>INS</i> 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.</p> Graphical Abstract <p></p>

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

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  • 发表日期：

    2026年3月3日

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  • 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

摘要

Aims/hypothesis

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.

Methods

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 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.

Results

LOF 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/interpretation

The 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