Likely inborn error of metabolism

Gene: WFS1

Comment on phenotypes: Previous phenotypes were: Diabetes with additional phenotypes suggestive of a monogenic aetiology;Inherited optic neuropathies;Wolfram syndrome 1, 222300;Mitochondrial respiratory chain disorders caused by nuclear variants only;Hereditary ataxia;Familial diabetes;Congenital hearing impairment (profound/severe)

Created: 6 May 2021, 9:40 a.m. | Last Modified: 6 May 2021, 9:40 a.m.

Panel Version: 2.131

PMID: 33693650 - Panfili et al 2021 - report an additional case of an 11 year old patient with Wolfram syndrome (diabetes mellitus and initial signs of optic atrophy) in which 2 novel variants in WFS1, c.316-1G > A (in intron 3) and c.757A > T (in exon 7), were identified by WES. Both are predicted to produce truncated and inactive protein. One variant was inherited from each parent. Most disease associated variants to date have been found in exon 8. Wildtype WFS1 protein was absent in peripheral blood mononuclear cells of the proband and there was no evidence of ER stress activation but very high levels of proinflammatory cytokines and a high ratio of proinflammatory T helper type 17 cells to regulatory T cells was found, suggesting that WFS1 deficiency may cause effects other than alterations in unfolded protein response (UPR) signaling pathways related to ER stress.

Created: 6 May 2021, 9:37 a.m. | Last Modified: 6 May 2021, 9:37 a.m.

Panel Version: 2.129

Publications

• 33693650

Green List (high evidence)

This gene was part of an initial gene list collated by Emma Ashton on behalf of the London North GLH, for GMS Metabolic Consensus Specialist Test Group. Additional information was not provided, such as mode of inheritance and phenotype. Promoted from Amber to Green. WFS1 is associated with an appropriate phenotype on OMIM and Gene2Phenotype. There are >3 unrelated cases listed on OMIM. Therefore, enough evidence for this gene to be promoted to Green status.

Created: 16 Oct 2019, 2:55 p.m. | Last Modified: 16 Oct 2019, 2:55 p.m.

Panel Version: 1.360

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Wolfram syndrome 1, 222300; Wolfram-like syndrome, autosomal dominant, 614296; Diabetes mellitus, noninsulin-dependent, association with, 125853

Publications

• 30171196

Red List (low evidence)

Initial gene list and info collated by Carl Fratter (Oxford University Hospitals NHS Trust) January 2019 on behalf of the GMS Mitochondrial specialist test group.

Created: 23 Jul 2019, 10:13 a.m. | Last Modified: 23 Jul 2019, 10:13 a.m.

Panel Version: 1.412