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

Aims/hypothesis Wolfram syndrome is a rare, autosomal recessive syndrome characterised by juvenile-onset diabetes and opticatrophy 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...

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Main Authors: Bansal, Vikas, Boehm, Bernhard O., Darvasi, Ariel
Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
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Language:English
Published: 2020
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Online Access:https://hdl.handle.net/10356/137250
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spelling sg-ntu-dr.10356-1372502020-11-01T05:12:59Z 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 Bansal, Vikas Boehm, Bernhard O. Darvasi, Ariel Lee Kong Chian School of Medicine (LKCMedicine) Science::Medicine Ashkenazi Jewish Carrier Screening Aims/hypothesis Wolfram syndrome is a rare, autosomal recessive syndrome characterised by juvenile-onset diabetes and opticatrophy 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 performthe 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 theWolfram 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 ofWolfram 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. MOE (Min. of Education, S’pore) Accepted version 2020-03-11T07:01:47Z 2020-03-11T07:01:47Z 2018 Journal Article Bansal, V., Boehm, B. O., & Darvasi, A. (2018). 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, 61, 2180–2188. doi:10.1007/s00125-018-4690-3 0012-186X https://hdl.handle.net/10356/137250 10.1007/s00125-018-4690-3 30014265 2-s2.0-85049939929 10 61 2180 2188 en Diabetologia © 2018 Springer-Verlag GmbH Germany, part of Springer Nature. All rights reserved. This paper was published in Diabetologia and is made available with permission of Springer-Verlag GmbH Germany, part of Springer Nature. application/pdf
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Science::Medicine
Ashkenazi Jewish
Carrier Screening
spellingShingle Science::Medicine
Ashkenazi Jewish
Carrier Screening
Bansal, Vikas
Boehm, Bernhard O.
Darvasi, Ariel
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
description Aims/hypothesis Wolfram syndrome is a rare, autosomal recessive syndrome characterised by juvenile-onset diabetes and opticatrophy 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 performthe 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 theWolfram 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 ofWolfram 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.
author2 Lee Kong Chian School of Medicine (LKCMedicine)
author_facet Lee Kong Chian School of Medicine (LKCMedicine)
Bansal, Vikas
Boehm, Bernhard O.
Darvasi, Ariel
format Article
author Bansal, Vikas
Boehm, Bernhard O.
Darvasi, Ariel
author_sort Bansal, Vikas
title 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
title_short 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_sort 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
publishDate 2020
url https://hdl.handle.net/10356/137250
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