A novel CISD2 intragenic deletion, optic neuropathy and platelet aggregation defect in Wolfram syndrome type 2
- Equal contributors
1 Department of Translational Medical Science, Section of Pediatrics, Regional Center of Pediatric Diabetology, University of Naples “Federico II”, Via S. Pansini 5, 80131 Naples, Italy
2 Pediatrics Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy
3 Medical Genetics Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy
4 Atherosclerosis and Thrombosis Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, FG, Italy
5 Laboratory of Diabetology - Laboratory for the Study of Inborn Errors of Metabolism, Pediatric Clinic, Regional Center of Pediatric Diabetology, Istituto Giannina Gaslini, Genova, Italy
6 Department of Molecular Medicine and Medical Biotechnology, University of Naples “Federico II”, Naples, Italy
7 Multidisciplinary Department of Medical, Surgical and Dental Sciences, Eye Clinic, Second University of Naples, Naples, Italy
BMC Medical Genetics 2014, 15:88 doi:10.1186/1471-2350-15-88Published: 24 July 2014
Wolfram Syndrome type 2 (WFS2) is considered a phenotypic and genotypic variant of WFS, whose minimal criteria for diagnosis are diabetes mellitus and optic atrophy. The disease gene for WFS2 is CISD2. The clinical phenotype of WFS2 differs from WFS1 for the absence of diabetes insipidus and psychiatric disorders, and for the presence of bleeding upper intestinal ulcers and defective platelet aggregation. After the first report of consanguineous Jordanian patients, no further cases of WFS2 have been reported worldwide. We describe the first Caucasian patient affected by WFS2.
The proband was a 17 year-old girl. She presented diabetes mellitus, optic neuropathy, intestinal ulcers, sensorineural hearing loss, and defective platelet aggregation to ADP. Genetic testing showed a novel homozygous intragenic deletion of CISD2 in the proband. Her brother and parents carried the heterozygous mutation and were apparently healthy, although they showed subclinical defective platelet aggregation. Long runs of homozygosity analysis from SNP-array data did not show any degree of parental relationship, but the microsatellite analysis confirmed the hypothesis of a common ancestor.
Our patient does not show optic atrophy, one of the main diagnostic criteria for WFS, but optic neuropathy. Since the “asymptomatic” optic atrophy described in Jordanian patients is not completely supported, we could suppose that the ocular pathology in Jordanian patients was probably optic neuropathy and not optic atrophy. Therefore, as optic atrophy is required as main diagnostic criteria of WFS, it might be that the so-called WFS2 could not be a subtype of WFS. In addition, we found an impaired aggregation to ADP and not to collagen as previously reported, thus it is possible that different experimental conditions or inter-patient variability can explain different results in platelet aggregation. Further clinical reports are necessary to better define the clinical spectrum of this syndrome and to re-evaluate its classification.