Elsevier

Genetics in Medicine

Volume 15, Issue 7, July 2013, Pages 497-506
Genetics in Medicine

Systematic Review
Genotypic classification of patients with Wolfram syndrome: insights into the natural history of the disease and correlation with phenotype

https://doi.org/10.1038/gim.2012.180Get rights and content
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Abstract

Purpose

Wolfram syndrome is a degenerative, recessive rare disease with an onset in childhood. It is caused by mutations in WFS1 or CISD2 genes. More than 200 different variations in WFS1 have been described in patients with Wolfram syndrome, which complicates the establishment of clear genotype–phenotype correlation. The purpose of this study was to elucidate the role of WFS1 mutations and update the natural history of the disease.

Methods

This study analyzed clinical and genetic data of 412 patients with Wolfram syndrome published in the last 15 years.

Results

(i) 15% of published patients do not fulfill the current ­inclusion criterion; (ii) genotypic prevalence differences may exist among countries; (iii) diabetes mellitus and optic atrophy might not be the first two clinical features in some patients; (iv) mutations are nonuniformly distributed in WFS1; (v) age at onset of diabetes mellitus, hearing defects, and diabetes insipidus may depend on the patient’s genotypic class; and (vi) disease progression rate might depend on genotypic class.

Conclusion

New genotype–phenotype correlations were established, disease progression rate for the general population and for the genotypic classes has been calculated, and new diagnostic criteria have been proposed. The conclusions raised could be important for patient management and counseling as well as for the development of treatments for Wolfram syndrome.

Genet Med 2013:15(7):497–506

Keywords

disease progression
genotype–phenotype correlation
mutation distribution
natural history
WFS1
Wolfram syndrome

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