Genotype-phenotype relationships in mucopolysaccharidosis type I (MPS I): Insights from the International MPS I Registry

Lorne A. Clarke, Roberto Giugliani, Nathalie Guffon, Simon A. Jones, Hillary A. Keenan, Maria V. Munoz-Rojas, Torayuki Okuyama, David Viskochil, Chester B. Whitley, Frits A. Wijburg, Joseph Muenzer

Research output: Contribution to journalArticlepeer-review

49 Scopus citations


Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder resulting from pathogenic variants in the α-L-iduronidase (IDUA) gene. Clinical phenotypes range from severe (Hurler syndrome) to attenuated (Hurler-Scheie and Scheie syndromes) and vary in age of onset, severity, and rate of progression. Defining the phenotype at diagnosis is essential for disease management. To date, no systematic analysis of genotype-phenotype correlation in large MPS I cohorts have been performed. Understanding genotype-phenotype is critical now that newborn screening for MPS I is being implemented. Data from 538 patients from the MPS I Registry (380 severe, 158 attenuated) who had 2 IDUA alleles identified were examined. In the 1076 alleles identified, 148 pathogenic variants were reported; of those, 75 were unique. Of the 538 genotypes, 147 (27%) were unique; 40% of patients with attenuated and 22% of patients with severe MPS I had unique genotypes. About 67.6% of severe patients had genotypes where both variants identified are predicted to severely disrupt protein/gene function and 96.1% of attenuated patients had at least one missense or intronic variant. This dataset illustrates a close genotype/phenotype correlation in MPS I but the presence of unique IDUA missense variants remains a challenge for disease prediction.

Original languageEnglish (US)
Pages (from-to)281-289
Number of pages9
JournalClinical Genetics
Issue number4
StatePublished - Oct 1 2019

Bibliographical note

Funding Information:
The authors are grateful to the patients and their families as well as the regional study centers for their continued participation in this registry. This study was supported by Sanofi Genzyme. The MPS I Registry is supported by Sanofi Genzyme.

Publisher Copyright:
© 2019 The Authors. Clinical Genetics published by John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


  • Scheie syndrome
  • genotype-phenotype
  • hurler syndrome
  • iduronidase
  • lysosomal storage disease
  • lysosome
  • metabolic disease
  • mucopolysaccharidosis


Dive into the research topics of 'Genotype-phenotype relationships in mucopolysaccharidosis type I (MPS I): Insights from the International MPS I Registry'. Together they form a unique fingerprint.

Cite this