Neonatal diabetes

Gene: FICD

Paper by Perera et al 2022 has now been published (PMID: 36704923).

There are also at least 3 other unrelated reports of diabetes mellitus and motor neuron disease due to biallelic variants at the Arg374 residue of FICD (PMID: 36136088; 40062579), but the age of onset in these cases is later than reported in the 2022 paper. Therefore this gene will be added to the R141 Monogenic diabetes (472) panel to cover the diabetes phenotype, as this panel (R143) is intended for patients with diabetes diagnosed less than 9 months of age.

Created: 13 Oct 2025, 4:09 p.m. | Last Modified: 13 Oct 2025, 4:09 p.m.

Panel Version: 5.3

Comment on list classification: Promoting from red to amber, but with a watchlist tag added.
3 cases reported but all with the same variant and 2 families share a common haplotype. Some functional data. In addition the paper is still at the pre-print stage and so has not yet been peer reviewed.

Created: 27 Sep 2022, 10:51 p.m. | Last Modified: 27 Sep 2022, 10:51 p.m.

Panel Version: 2.53

Gene does not appear to be in OMIM.

As expert reviewer reports the pre-print by Perera et al 2022 report 5 individuals, from 3 consanguineous families, diagnosed with infancy-onset diabetes mellitus and neurodevelopmental abnormalities (4/5 had severe developmental delay). Age of diabetes onset was a mean of 29 weeks (range 12-43). All were found to have a homozygous variant p.(Arg371Ser) mutation in FICD. Family 1 and Family 3 where found to share a 4.5Mb haplotype that includes FICD which suggests the variant was inherited from a common distant ancestor. Functional studies showed that the variant partially compromises BiP AMPylation in vitro and eliminates all
detectable deAMPylation activity.

Created: 27 Sep 2022, 10:45 p.m. | Last Modified: 27 Sep 2022, 11:44 p.m.

Panel Version: 2.57

Review on behalf of Jayne Houghton and Kevin Colclough, Exeter Genomics Laboratory, SWGLH. Perera et al 2022 (medRxiv preprint doi: https://doi.org/10.1101/2022.05.14.22275020) reported a genetic syndrome of neonatal diabetes, severe developmental delay and skeletal abnormalities due to a homozygous variant, p.(Arg371Ser), in the FICD gene in 5 affected individuals from 3 different families. The disease mechanism likely consists of an intra-organellar perturbation that compromises both insulin-producing beta cells and cells relevant to neurological development and/or function. Functional studies of the specific variant identified in the reported families to date suggests a variant-specific mechanism, causing inappropriately elevated levels of AMPylated BiP as opposed to overall loss of gene function.

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, severe neurodevelopmental delay and skeletal abnormalities.