Neonatal diabetes

Gene: ZNF808

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to 'BIALLELIC, autosomal or pseudoautosomal' following NHS Genomic Medicine Service approval.

Created: 31 Jan 2023, 4:43 p.m. | Last Modified: 31 Jan 2023, 4:43 p.m.

Panel Version: 3.3

Comment on list classification: Promoting from red to amber, with a recommendation for GREEN rating following GMs review. Paper not yet published but from GLH source.

Created: 11 Oct 2022, 12:17 p.m. | Last Modified: 11 Oct 2022, 12:17 p.m.

Panel Version: 2.60

The ZNF808 gene does not appear in OMIM and there is no gene-disease association for this gene in Gene2Phenotype.

As the reviewer describes, De Franco et al 2022 (https://www.medrxiv.org/content/10.1101/2021.08.23.21262262v1) report 12 unrelated cases of probands with neonatal diabetes before the age of 6 months in which homozygous variants in ZNF808 have been identified. These were initially identified in 2 unrelated probands from consanguineous unions and then 232 additional neonatal diabetes patients without an identified cause were screened for variants in ZNF808 and a further 10 cases were identified. A variety of variants were identified including deletions (exons 4 and 5, whole gene deletion), nonsense and frameshift variants. Although this paper is not yet published it is from well respected authors including members of the Exeter Genomic Laboratory Hub.

Created: 28 Sep 2022, 12:10 p.m. | Last Modified: 28 Sep 2022, 12:11 p.m.

Panel Version: 2.57

Review on behalf of Jayne Houghton and Kevin Colclough, Exeter Genomics Laboratory, SWGLH. De Franco et al 2022 (Nature Genetics submitted and medRxiv preprint doi: https://www.medrxiv.org/content/10.1101/2021.08.23.21262262v1) ZNF808 biallelic loss-of-function variants cause a pancreatic specific development defect affecting both exocrine and endocrine function resulting in neonatal diabetes and exocrine pancreatic insufficiency which often presents clinically as malabsorption. To date 12 unrelated patients diagnosed with neonatal diabetes before the age of 6 months have been identified with homozygous loss-of-function variants (nonsense, frameshift and whole gene deletions) without an identified pathogenic variant in the other known aetiological genes. Parental testing confirmed that all unaffected parents were heterozygous carriers.

Created: 14 Sep 2022, 4:42 p.m. | Last Modified: 14 Sep 2022, 4:42 p.m.

Panel Version: 2.40

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Phenotypes
neonatal diabetes mellitus, MONDO:0016391; pancreatic agenesis, MONDO:0009832