Genotype-phenotype Relationships in Mucopolysaccharidosis Type I (MPS I): Insights from the International MPS I Registry

Overview

Journal Clin Genet

Specialty Genetics

Date 2019 Jun 14

PMID 31194252

Citations 33

Authors

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

Affiliations

Soon will be listed here.

Abstract

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.

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