Genotype-phenotype relationships in mucopolysaccharidosistype I (MPS I) : insights from the International MPS I Registry

Abstract

Mucopolysaccharidosis type I (MPS I) is a rare autosomal recessive disorder resultingfrom pathogenic variants in theα-L-iduronidase (IDUA) gene. Clinical phenotypesrange from severe (Hurler syndrome) to attenuated (Hurler-Scheie and Scheie syn-dromes) and vary in age of onset, severity, and rate of progression. Defining the phe-notype at diagnosis is essential for disease management. To date, no systematicanalysis of genotype-phenotype correlation in large MPS I cohorts have been per-formed. Understanding genotype-phenotype is critical now that newborn screeningfor MPS I is being implemented. Data from 538 patients from the MPS I Registry(380 severe, 158 attenuated) who had 2IDUAalleles identified were examined. Inthe 1076 alleles identified, 148 pathogenic variants were reported; of those, 75 wereunique. Of the 538 genotypes, 147 (27%) were unique; 40% of patients with attenu-ated and 22% of patients with severe MPS I had unique genotypes. About 67.6% ofsevere patients had genotypes where both variants identified are predicted toseverely disrupt protein/gene function and 96.1% of attenuated patients had at leastone missense or intronic variant. This dataset illustrates a close genotype/phenotypecorrelation in MPS I but the presence of uniqueIDUAmissense variants remains achallenge for disease prediction.