ONECUT1 (also known as HNF6) is a transcription factor involved in pancreatic development and β-cell function. Recently, biallelic variants in ONECUT1 were reported as a cause of neonatal diabetes mellitus (NDM) in two subjects, and missense monoallelic variants were associated with type 2 diabetes and possibly maturity-onset diabetes of the young (MODY). Here we examine the role of ONECUT1 variants in NDM, MODY, and type 2 diabetes in large international cohorts of subjects with monogenic diabetes and >400,000 subjects from UK Biobank. We identified a biallelic frameshift ONECUT1 variant as the cause of NDM in one individual. However, we found no enrichment of missense or null ONECUT1 variants among 484 individuals clinically suspected of MODY, in whom all known genes had been excluded. Finally, using a rare variant burden test in the UK Biobank European cohort, we identified a significant association between heterozygous ONECUT1 null variants and type 2 diabetes (P = 0.006) but did not find an association between missense variants and type 2 diabetes. Our results confirm biallelic ONECUT1 variants as a cause of NDM and highlight monoallelic null variants as a risk factor for type 2 diabetes. These findings confirm the critical role of ONECUT1 in human β-cell function.

Article Highlights
  • We confirmed homozygous ONECUT1 variants as causative for neonatal diabetes with the identification of a third case.

  • Rare heterozygous ONECUT1 variants were not enriched in a cohort of 484 individuals clinically suspected of having maturity-onset diabetes of the young.

  • Heterozygous null ONECUT1 variants are significantly associated with type 2 diabetes in the UK Biobank European population.

  • No association was observed between heterozygous ONECUT1 missense variants and type 2 diabetes in UK Biobank.

This article contains supplementary material online at https://doi.org/10.2337/figshare.24018558.

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