Monogenic diabetes

Gene: WFS1

Green List (high evidence)

Comment on phenotypes: Phenotypes updated 27th Feb 2026.

Created: 27 Feb 2026, 10:55 a.m. | Last Modified: 27 Feb 2026, 10:55 a.m.

Panel Version: 3.10

PMID: 40779032 Sriram et al., 2025
Cohort of 2,571 unrelated individuals of European ancestry with clinically suspected MODY. Genes assessed: APPL1 NM_012096.3, HNF1A NM_000545.8, NEUROD1 NM_002500.5, PDX1 NM_000209.4, RFX6 NM_173560.4, and WFS1 NM_006005.3.
"Frequency and co-segregation analysis examined specific, previously published variants and did not assess if other rare variants in these genes cause MODY."
- MODY cohort showed no enrichment for protein-truncating variants or damaging missense variants in WFS1 (p > 0.05). Other genes (NEUROD1 and PDX1) showed enrichment in the MODY cohort.
- Study identified a WFS1 p.Trp314Arg carrier: diagnosed with diabetes at age 33, BMI 22.9, no family history of diabetes, no known other pathogenic variant.

PMID: 39221226 Wu et al., 2024
Whole exome seq in 165 early-onset diabetes patients. Detected WFS1 compound heterozygous variants in two patients with Wolfram Syndrome-Like disorders.
WFS1 heterozygous variants were identified in patients P3-P5: c.1289C>T, p.S430L; c.1552A>G, p.M518V; c.676C>T, p.Q226*. All variants in this study affect exons 6 or 8 of WFS1. Heterozygous patients all had family history of diabetes, and were all diagnosed at 25 years old. Diagnosed with MODY rather than Wolfram Syndrome.
P1: female, diagnosed with diabetes at age 25years, compound het for WFS1 c.639_640dupGG, p.A214fs*74/c.985T>A, p.F329I; mother and father heterozygous for a variant each (both diagnosed with diabetes over age 35 years). Some affected family members were carriers of either variant, some had neither. Proband did not present with ketoacidosis, optic atrophy, deafness, or diabetes insipidus.
P2: female, diagnosed with diabetes at 13yo, compound het for WFS1 c.1280T>G, p.I427S/c.911T>C, p.I304T; no neurological, psychiatric, or high-frequency hearing issues, or optic nerve atrophy; brother, mother and father were heterozygous for a WFS1 variant each, not affected.

Functional analysis verified the impaired function of the WFS1 compound heterozygous variants: p.A214fs*74 and p.I427S significantly reduced wolframin levels (absent/near absent); p.I427S and the compound heterozygous p.I427S/p.I304T variants significantly activated the ERSE reporter, indicating high ER stress

PMID: 29207974 Bansal et al., 2017
Sequenced 22 diabetes related genes in almost 7000 individuals. Identified an individual with early onset diabetes (onset at 14 years old; no additional phenotypes associated with Wolfram syndrome), homozygous for WFS1: c.1672C > T; p.R558C.

PMID: 28271591 Morikawa et al. 2017
Japanese female patient with a de novo heterozygous WFS1 c.973_984del12, p.Asn325_Ile328del variant (not in gnomAD v4.1.0. She presented with impaired growth, bilateral congenital cataracts, severe hypermetropia, severe bilateral hearing loss, delayed development, insulin dependent diabetes mellitus - diagnosed with Wolfram Syndrome. In vitro testing showed that the WFS1 variant has a dominant negative effect, increasing ER stress.

PMID: 23903355 Bonnycastle et al., 2013
Large Finnish pedigree with AD diabetes, WFS1 p.Trp314Arg variant co-segregated completely with disease. Seq method: exome/Sanger. Age of diabetes onset ranged from 18 to 51 years. No history of ketoacidosis, 7/8 affected individuals treated with insulin. Functionally p.Trp314Arg appears to reduce the ability of WFS1 to protect against ER stress (study in HEK293T cells).

WFS1 is associated with AR Wolfram syndrome 1, OMIM:222300 (OMIM accessed 27th Feb 2026). The gene-disease associations between WFS1 and AR Wolfram syndrome, AD Wolfram-like syndrome, and AD Nonsyndromic hearing loss are all classified as Definitive in ClinGen.

Created: 27 Feb 2026, 10:51 a.m. | Last Modified: 27 Feb 2026, 10:54 a.m.

Panel Version: 3.8

Mode of inheritance
BOTH monoallelic and biallelic (but BIALLELIC mutations cause a more SEVERE disease form), autosomal or pseudoautosomal

Phenotypes
Wolfram syndrome 1, OMIM:222300; Wolfram syndrome 1, MONDO:0009101; Wolfram-like syndrome, MONDO:0013673

Publications

• 23903355
• 28271591
• 29207974
• 39221226
• 40779032

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: 5 May 2021, 5:53 p.m. | Last Modified: 5 May 2021, 5:53 p.m.

Panel Version: 2.41

Publications

• 33693650

Green List (high evidence)

Comment on phenotypes: Previous phenotypes:
diabetes insipidus or optic atrophy;Wolfram-like syndrome, autosomal dominant, 614296;Deafness, autosomal dominant 6/14/38, 600965;{Diabetes mellitus, noninsulin-dependent,association with};Deafness,autosomal dominant 6/14/38, 600965;Wolfram syndrome, 222300;{Diabetes mellitus, noninsulin-dependent, association with}, 125853;?Cataract 41,116400

Created: 16 Mar 2021, 2:31 p.m. | Last Modified: 16 Mar 2021, 2:31 p.m.

Panel Version: 2.38

Initial gene list and info collated by Sian Ellard, University of Exeter Medical School, August 2018 on behalf of the GMS Endocrinology specialist test group. Gene Symbol submitted: WFS1; Suggested intial gene rating: Green; Evidence for inclusion: none given; Evidence for exclusion: none given; Technical notes (e.g. non-coding/CNV mutations requiring coverage?): none given; Phenotypes: Wolfram syndrome

Created: 11 Jan 2019, 10:04 a.m.

Green List (high evidence)

Mode of inheritance
BIALLELIC, autosomal or pseudoautosomal

Variants in this GENE are reported as part of current diagnostic practice

Comment on mode of inheritance: Biallelic WFS1 variants are most commonly associated with Wolfram syndrome. However, heterozygous dominant negative WFS1 variants are associated with a rare form of Wolfram syndrome with subtle phenotypic differences. Comment from Sian Ellard (paper in preparation)

Created: 5 Jul 2016, 7:46 a.m.

Comment on mode of inheritance: Changed from 'other' to both to capture these variants in tiering.

Created: 3 Apr 2017, 5:05 p.m.

Comment on list classification: Promoted from red to green due to expert review and further supporting evidence on OMIM.

Created: 28 Jun 2016, 3:11 p.m.