Loss of function variants in the primate-specific gene ZNF808 cause neonatal, transient and adult-onset diabetes.

BACKGROUND

Biallelic loss-of-function ZNF808 variants were recently identified as a cause of pancreatic agenesis characterised by insulin-treated permanent neonatal diabetes (PNDM), low birthweight and exocrine pancreatic insufficiency.

METHODS

We investigated the phenotypic diversity caused by biallelic loss-of-function ZNF808 variants by screening a cohort of 4699 individuals with genetically undiagnosed monogenic diabetes: 335 with neonatal diabetes (NDM, diagnosed <6 months), 194 with infancy-onset diabetes (diagnosed 6-12 months) and 4170 diagnosed with diabetes between 1 and 60 years of age.

FINDINGS: Through a combination of genome and targeted next-generation-sequencing, we identified 17 previously unreported individuals with biallelic loss-of-function ZNF808 variants, bringing the total number of cases identified in the Exeter cohort to 31 when combined with previously described cases. 30/31 individuals were born to related parents. Clinically, 19 had PNDM, whilst the remaining 12 had other diabetes phenotypes: 5 with infancy-onset diabetes, 4 with transient diabetes and 3 with diabetes diagnosed aged 10, 14 and 23 years. Individuals with ZNF808-diabetes did not always require insulin treatment, with sulphonylurea treatment reported in 3 individuals. Exocrine pancreatic function was not consistently affected across the cohort, with no clinical features of exocrine insufficiency reported in 17 individuals and normal exocrine function biochemically confirmed in one further individual.

INTERPRETATION: Biallelic loss of ZNF808 results in a variable pancreatic phenotype ranging from pancreatic agenesis to adult-onset diabetes without exocrine insufficiency. ZNF808 gene testing should be considered in individuals with diabetes diagnosed after the neonatal period, especially if born to related parents.

FUNDING: Wellcome Trust, Diabetes UK.