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Review
. 2021 Apr 30;18(9):4796.
doi: 10.3390/ijerph18094796.

Clinical Spectrum Associated with Wolfram Syndrome Type 1 and Type 2: A Review on Genotype-Phenotype Correlations

Maurizio Delvecchio  1 , Matteo Iacoviello  2 , Antonino Pantaleo  2 , Nicoletta Resta  2
Affiliations
Review

Clinical Spectrum Associated with Wolfram Syndrome Type 1 and Type 2: A Review on Genotype-Phenotype Correlations

Maurizio Delvecchio et al. Int J Environ Res Public Health. .

Abstract

Wolfram syndrome is a rare neurodegenerative disorder that is typically characterized by diabetes mellitus and optic atrophy. Other common features are diabetes insipidus and hearing loss, but additional less-frequent findings may also be present. The phenotype spectrum is quite wide, and penetrance may be incomplete. The syndrome is progressive, and thus, the clinical picture may change during follow-up. Currently, two different subtypes of this syndrome have been described, and they are associated with two different disease-genes, wolframin (WFS1) and CISD2. These genes encode a transmembrane protein and an endoplasmic reticulum intermembrane protein, respectively. These genes are detected in different organs and account for the pleiotropic features of this syndrome. In this review, we describe the phenotypes of both syndromes and discuss the most pertinent literature about the genotype-phenotype correlation. The clinical presentation of Wolfram syndrome type 1 suggests that the pathogenic variant does not predict the phenotype. There are few papers on Wolfram syndrome type 2 and, thus, predicting the phenotype on the basis of genotype is not yet supported. We also discuss the most pertinent approach to gene analysis.

Keywords: CISD2; ERIS; Wolfram syndrome; diabetes insipidus; diabetes mellitus; genotype-phenotype correlation; molecular genetics; optic atrophy; sensorineural hearing loss; wolframin.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Flow diagram for article selection.
Figure 2
Figure 2
Genetic variant distribution in WFS1. Adapted from Alamut Visual version 2.15 (SOPHiA GENETICS, Lausanne, Switzerland) and from VarSome: The Human Genomic Variant Search Engine. Christos Kopanos, Vasilis Tsiolkas, Alexandros Kouris, Charles E. Chapple, Monica Albarca Aguilera, Richard Meyer, and Andreas Massouras. Oxford Bioinformatics, bty897, 30 October 2018. doi:10.1093/bioinformatics/bty897.
Figure 3
Figure 3
Genetic variant distribution in CISD2. Adapted from Alamut Visual version 2.15 (SOPHiA GENETICS, Lausanne, Switzerland) and from VarSome: The Human Genomic Variant Search Engine. Christos Kopanos, Vasilis Tsiolkas, Alexandros Kouris, Charles E. Chapple, Monica Albarca Aguilera, Richard Meyer, and Andreas Massouras. Oxford Bioinformatics, bty897, 30 October 2018. doi:10.1093/bioinformatics/bty897.
See this image and copyright information in PMC

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