The Role of ONECUT1 Variants in Monogenic and Type 2 Diabetes Mellitus

This is the author accepted manuscript. The final version is available from the American Diabetes Association via the DOI in this recordData and Resource Availability: The monogenic diabetes patient data used in this study are available from the corresponding author upon reasonable request. The type 2 diabetes data used in this study are available via UK Biobank (https://www.ukbiobank.ac.uk/), subject to necessary approvals.ONECUT1 (also known as HNF6) is a transcription factor involved in pancreatic development and beta-cell function. Recently, biallelic variants in ONECUT1 were reported as a cause of neonatal diabetes mellitus (NDM) in 2 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 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 beta-cell function.Diabetes UKMedical Research Council (MRC)Wellcome TrustNational Institute for Health Research (NIHR

A biallelic loss-of-function PDIA6 variant in a second patient with polycystic kidney disease, infancy-onset diabetes, and microcephaly

This is the final version. Available on open access from Wiley via the DOI in this recordData Availability Statement: Data available from the corresponding author upon reasonable request.We report a second patient with intrauterine growth retardation, congenital polycystic kidney disease, infancy-onset diabetes, microcephaly, and liver fibrosis caused by a homozygous PDIA6 loss-of-function variant. Our study further defines the genetic and clinical features of this rare syndromic form of infancy-onset diabetes.Diabetes UKWellcome Trus