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IDUA mutational profile and genotype-phenotype relationships in UK patients with Mucopolysaccharidosis Type I.

Authors
  • Ghosh, Arunabha1, 2
  • Mercer, Jean1
  • Mackinnon, Sabrina3
  • Yue, Wyatt W3
  • Church, Heather1
  • Beesley, Clare E4
  • Broomfield, Alex1
  • Jones, Simon A1
  • Tylee, Karen1
  • 1 Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester Academic Health Science Centre (MAHSC), Manchester, UK.
  • 2 School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK.
  • 3 Structural Genomics Consortium, Nuffield Department of Medicine, University of Oxford, London, UK.
  • 4 North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
Type
Published Article
Journal
Human Mutation
Publisher
Wiley (John Wiley & Sons)
Publication Date
Nov 01, 2017
Volume
38
Issue
11
Pages
1555–1568
Identifiers
DOI: 10.1002/humu.23301
PMID: 28752568
Source
Medline
Keywords
License
Unknown

Abstract

Mucopolysaccharidosis Type I (MPS I) is a lysosomal storage disorder with varying degrees of phenotypic severity caused by mutations in IDUA. Over 200 disease-causing variants in IDUA have been reported. We describe the profile of disease-causing variants in 291 individuals with MPS I for whom IDUA sequencing was performed, focusing on the UK subset of the cohort. A total of 63 variants were identified, of which 20 were novel, and the functional significance of the novel variants is explored. The severe form of MPS I is treated with hematopoietic stem cell transplantation, known to have improved outcomes with earlier age at treatment. Developing genotype-phenotype relationships would therefore have considerable clinical utility, especially in the light of the development of newborn screening programs for MPS I. Associations between genotype and phenotype are examined in this cohort, particularly in the context of the profile of variants identified in UK individuals. Relevant associations can be made for the majority of UK individuals based on the presence of nonsense or truncating variants as well as other associations described in this report.

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