Abstract
Mucopolysaccharidosis type II (Hunter syndrome, MPS II) is an X-linked lysosomal storage disorder caused by the deficit of iduronate 2-sulfatase (IDS), an enzyme involved in the glycosaminoglycans (GAGs) degradation. We here report the case of a 9-year-old boy who was diagnosed with an extremely severe form of MPS II at 10 months of age. Sequencing of the IDS gene revealed the deletion of exons 1–7, extending distally and removing the entire pseudogene IDSP1. The difficulty to define the boundaries of the deletion and the particular severity of the patient phenotype suggested to verify the presence of pathological copy number variations (CNVs) in the genome, by the array CGH (aCGH) technology. The examination revealed the presence of two deletions alternate with two duplications, overall affecting a region of about 1.2 Mb distally to IDS gene. This is the first complex rearrangement involving IDS and extending to a large region located distally to it described in a severe Hunter patient, as evidenced by the CNVs databases interrogated. The analysis of the genes involved in the rearrangement and of the disorders correlated with them did not help to clarify the phenotype observed in our patient, except for the deletion of the IDS gene, which explains per se the Hunter phenotype. However, this cannot exclude a potential “contiguous gene syndrome” as well as the future rising of additional pathological symptoms associated with the other extra genes involved in the identified rearrangement.
Competing interests: None declared
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Acknowledgments
Part of the data in this manuscript were obtained from the ISCA Consortium database (www.iscaconsortium.org), which generates this information using NCBI's database of genomic structural variation (dbVar, www.ncbi.nlm.nih.gov/dbvar/), study nstd37. Samples and associated phenotype data were provided by ISCA Consortium member laboratories.
This study makes use of data generated by the DECIPHER Consortium. A full list of centers who contributed to the generation of the data is available from http://decipher.sanger.ac.uk and via email from decipher@sanger.ac.uk. Funding for the project was provided by the Wellcome Trust.
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Communicated by: Gregory M. Pastores, MD
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First case described of a Hunter patient with two deletions alternate with two duplications, involving exons 1–7 of the IDS gene and extending 1.2 Mb distally to it.
Details of the contributions of individual authors
AZ: conception and design of the study, performing of IDS molecular analysis, analysis and interpretation of molecular data, writing and critical revision of the manuscript. RT: conception and design of the study, clinical data collection, writing and critical revision of the manuscript. AR: clinical data collection and analysis, critical revision of the manuscript. CR: aCGH analysis, interpretation of aCGH data, critical revision of the manuscript. NG: urinary GAG analyses, critical revision of the manuscript. MCa: critical revision of the manuscript. MCl: critical revision of the manuscript. MS: conception and design of the study, critical revision of the manuscript, final approval of the manuscript.
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Maurizio Scarpa.
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No funding was raised to conduct this study.
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Ethics approval was not required to perform the described studies.
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Informed consent for genetic analyses in the patient and relatives was obtained from the subject involved in the study, parents or tutors.
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Maurizio Scarpa has received research grants and honoraria and travel support for speaking engagements from Actelion, Shire HGT, Genzyme Corporation, and BioMarin.
Alessandra Zanetti, Rosella Tomanin, Angelica Rampazzo, Chiara Rigon, Nicoletta Gasparotto, Matteo Cassina, and Maurizio Clementi declare no conflicts of interest.
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Zanetti, A. et al. (2014). A Hunter Patient with a Severe Phenotype Reveals Two Large Deletions and Two Duplications Extending 1.2 Mb Distally to IDS Locus. In: Zschocke, J., Gibson, K., Brown, G., Morava, E., Peters, V. (eds) JIMD Reports, Volume 17. JIMD Reports, vol 17. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2014_317
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DOI: https://doi.org/10.1007/8904_2014_317
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