Identification of a missense variant in the WFS1 gene that causes a mild form of Wolfram syndrome and is associated with risk for type 2 diabetes in Ashkenazi Jewish individuals

Diabetologia. 2018 Oct;61(10):2180-2188. doi: 10.1007/s00125-018-4690-3. Epub 2018 Jul 16.


Aims/hypothesis: Wolfram syndrome is a rare, autosomal recessive syndrome characterised by juvenile-onset diabetes and optic atrophy and is caused by bi-allelic mutations in the WFS1 gene. In a recent sequencing study, an individual with juvenile-onset diabetes was observed to be homozygous for a rare missense variant (c.1672C>T, p.R558C) in the WFS1 gene. The aim of this study was to perform the genetic characterisation of this variant and to determine whether it is causal for young-onset diabetes and Wolfram syndrome.

Methods: We analysed the allele frequency of the missense variant in multiple variant databases. We genotyped the variant in 475 individuals with type 1 diabetes and 2237 control individuals of Ashkenazi Jewish ancestry and analysed the phenotypes of homozygotes. We also investigated the association of this variant with risk for type 2 diabetes using genotype and sequence data for type 2 diabetes cases and controls.

Results: The missense variant demonstrated an allele frequency of 1.4% in individuals of Ashkenazi Jewish ancestry, 60-fold higher than in other populations. Genotyping of this variant in 475 individuals diagnosed with type 1 diabetes identified eight homozygotes compared with none in 2237 control individuals (genotype relative risk 135.3, p = 3.4 × 10-15). The age at diagnosis of diabetes for these eight individuals (17.8 ± 8.3 years) was several times greater than for typical Wolfram syndrome (5 ± 4 years). Further, optic atrophy was observed in only one of the eight individuals, while another individual had the Wolfram syndrome-relevant phenotype of neurogenic bladder. Analysis of sequence and genotype data in two case-control cohorts of Ashkenazi ancestry demonstrated that this variant is also associated with an increased risk of type 2 diabetes in heterozygotes (OR 1.81, p = 0.004).

Conclusions/interpretation: We have identified a low-frequency coding variant in the WFS1 gene that is enriched in Ashkenazi Jewish individuals and causes a mild form of Wolfram syndrome characterised by young-onset diabetes and reduced penetrance for optic atrophy. This variant should be considered for genetic testing in individuals of Ashkenazi ancestry diagnosed with young-onset non-autoimmune diabetes and should be included in Ashkenazi carrier screening panels.

Keywords: Ashkenazi Jewish; Carrier screening; Genetic testing; Juvenile-onset diabetes; Optic atrophy; Type 1 diabetes; Type 2 diabetes; Wolfram syndrome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Age of Onset
  • Alleles
  • Diabetes Mellitus, Type 1 / ethnology
  • Diabetes Mellitus, Type 1 / genetics
  • Diabetes Mellitus, Type 2 / ethnology*
  • Diabetes Mellitus, Type 2 / genetics*
  • Female
  • Gene Frequency
  • Genetic Variation
  • Genotype
  • Haplotypes
  • Heterozygote
  • Homozygote
  • Humans
  • Jews
  • Male
  • Membrane Proteins / genetics*
  • Mutation, Missense*
  • Optic Atrophy / pathology
  • Phenotype
  • Risk
  • Wolfram Syndrome / ethnology*
  • Wolfram Syndrome / genetics*
  • Young Adult


  • Membrane Proteins
  • wolframin protein