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March 5, 2026Diabetologia2 citationsOpen Access

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

TLThomas W. LaverASAparajita SriramMWMatthew N. Wakeling

Key Points

  • The research aims to evaluate the pathogenic effects of loss-of-function variants in MODY genes, focusing on their implications for diagnosis.
  • Systematic analysis of loss-of-function variants across multiple MODY genes.
  • Focus on gene context and NMD (nonsense-mediated decay) status.
  • Comparison of heterozygous NMD-escape variants with other MODY causes.
  • Identified heterozygous NMD-escape LOF variants in INS as a new cause of MODY.
  • Demonstrated variability in pathogenicity based on gene context.
  • Expanded the understanding of INS variants affecting MODY diagnosis.

Abstract

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.

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Cite This Study

Laver et al. (2026) studied this question.

synapsesocial.com/papers/69a91e4cd6127c7a504c21cbhttps://doi.org/10.1007/s00125-026-06685-7
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Also Consider

Synapse has enriched 5 closely related papers on similar clinical questions. Consider them for comparative context:

  1. 1Systematic analysis of loss-of-function variants across MODY genes demonstrates gene- and NMD-specific effects and identifies NMD-escape <i>INS</i> variants as a novel cause of MODY2025
  2. 2Insights into INS Gene Variation from Seven Years of Monogenic Diabetes Testing—Novel Genetic Variants and Their Clinical Implications2026
  3. 3The Importance of Molecular Genetic Testing for Precision Diagnostics, Management, and Genetic Counseling in MODY Patients2024 · 4 citations
  4. 4Mutational landscapes of HNF MODY gene products display a wide distribution with functional implications2025
  5. 5Rare variants in&lt;i&gt; NEUROD1&lt;/i&gt; and &lt;i&gt;PDX1&lt;/i&gt; are low penetrance causes of MODY, whereas those in &lt;i&gt;APPL1&lt;/i&gt; and &lt;i&gt;WFS1&lt;/i&gt; are not associated with MODY2025