Human Mutation
Human Mutation
4 years ago

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

IDUA mutational profile and genotype–phenotype relationships in UK patients with Mucopolysaccharidosis Type I
Sabrina Mackinnon, Simon A Jones, Arunabha Ghosh, Jean Mercer, Alex Broomfield, Wyatt W Yue, Heather Church, Karen Tylee, Clare E Beesley
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. Positions of residues within the structure of alpha-iduronidase affected by five novel missense variants. In this study, we sequenced IDUA in 291 individuals with Mucopolysaccharidosis Type I (MPS I) and identified 63 variants (20 novel). Pathogenicity of novel variants was examined using in silico tools and structural analysis. Associations between genotype and phenotypic severity were made for the majority of variants observed in the cohort, which will be relevant in the development of newborn screening for MPS I.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/humu.23301

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