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(10): 2180-2188, 2018 10.
Article
em En
| MEDLINE
| ID: mdl-30014265
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.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Síndrome de Wolfram
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Mutação de Sentido Incorreto
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Diabetes Mellitus Tipo 2
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Proteínas de Membrana
Tipo de estudo:
Diagnostic_studies
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Etiology_studies
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Risk_factors_studies
Limite:
Adolescent
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Adult
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Female
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Humans
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Male
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article