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
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.
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.
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).
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.
KeywordsAshkenazi Jewish Carrier screening Genetic testing Juvenile-onset diabetes Optic atrophy Type 1 diabetes Type 2 diabetes Wolfram syndrome
65 kDa isoform of GAD
Hebrew University Genetic Resource
The Ashkenazi Jewish T2D-GENES data used in this study was obtained from the NIH dbGaP repository (study accession phs001095.v1.p1) and supplied by the Albert Einstein College of Medicine and Broad Institute. The Ashkenazi T2D-GENES Sequencing study was conducted by the Ashkenazi T2D-GENES Sequencing study investigators and supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). We thank R. Blagieva, S. Claudi-Boehm, B. Manfras and W. Kratzer (University of Ulm, Germany) for phenotyping.
VB conceived the project, obtained sequence and genotype data, analysed and interpreted the data and wrote the manuscript. BOB acquired phenotype data and reviewed and edited the manuscript. AD acquired genotype and phenotype data, contributed to interpretation of the data and reviewed and edited the manuscript. All authors approved the final version of the manuscript. VB is the guarantor of this work, had full access to all the data in the study and takes responsibility for the integrity of the data and accuracy of the data analysis.
This project was supported by start-up funds from the Department of Pediatrics at the University of California San Diego and a gift from Rady Children’s Hospital, San Diego to VB. BOB is supported by the Lee Kong Chian School of Medicine, Nanyang Technological University Start Up Grant MOE AcRF Tier 1 (2015-T1–001-258), NTU-NHG Metabolic Diseases Collaboration Grant (MDCG/15006), Deutsche Forschungsgemeinschaft (DFG, GrK 1041) and State Baden-Wuerttemberg, Germany.
Duality of interest
The authors declare that there is no duality of interest associated with this manuscript.
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