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Diabetologia
Erschienen in: Diabetologia 10/2018

16.07.2018 | Article

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

verfasst von: Vikas Bansal, Bernhard O. Boehm, Ariel Darvasi

Erschienen in: Diabetologia | Ausgabe 10/2018

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Abstract

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.
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Metadaten
Titel
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
verfasst von
Vikas Bansal
Bernhard O. Boehm
Ariel Darvasi
Publikationsdatum
16.07.2018
Verlag
Springer Berlin Heidelberg
Erschienen in
Diabetologia / Ausgabe 10/2018
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI
https://doi.org/10.1007/s00125-018-4690-3

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