Systematic analysis of loss-of-function variants across MODY genes demonstrates gene-specific effects and expands the spectrum of INS variants causing MODY
Authors' conclusion
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.
Study context
- Population
- Individuals of European ancestry with suspected MODY; ultra-rare loss-of-function (LOF) variants (minor allele frequency <1 in 10,000) in 10 MODY genes, classified as nonsense-mediated decay (NMD)-triggering or NMD-escape
- Participants
- 5,171 vs 155,501
- Comparison
- Suspected MODY cases vs UK Biobank population controls
- Suspected MODYn = 5,171
- Controlsn = 155,501reference
- Outcome
- Gene-level enrichment of LOF variants in cases vs controls, stratified by NMD status
Methodological detailsgene-level enrichment analysis, replication, familial co-segregation, in silico protein modelling
- Gene-level enrichment analysis
- Replication
- Familial co-segregation
- In silico protein modelling
Main finding
As reported in the abstract
Gene-level enrichment of ultra-rare LOF variants in suspected MODY cases vs population controls, by NMD status
- Both NMD-triggering and NMD-escape variants enriched in GCK, HNF1A and HNF4A, consistent with haploinsufficiency
- all p<10-3
- INS: significant enrichment of only NMD-escape LOF variants (novel finding)
- OR=181, p<10-5
Observational data: associations, not effects.
Further findings
INS variant carriers (incl. replication)
- Families with INS variants
- 8 families, 17 affected individuals
- Co-segregation with diabetes, logarithm of the odds score
- 3
- De novo case
- 1
- Absent from population control individuals
- >800,000
- Median age at diabetes presentation
- 19 years
- Median BMI
- 22.9 kg/m²
- Islet autoantibody negative; low T1D genetic risk scores
- Diagnosis vs INS missense MODY: ≈10 years later with NMD-escape LOF variants
In silico protein modelling
- INS NMD-escape variants suggested to produce aberrant proinsulin with unpaired B-chain cysteines, leading to milder misfolding
Original publication
Systematic analysis of loss-of-function variants across MODY genes demonstrates gene-specific effects and expands the spectrum of INS variants causing MODY. Diabetologia. Published 3 March 2026. doi:10.
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