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

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.

Incorporation of Second-Tier Biomarker Testing Improves the Specificity of Newborn Screening for Mucopolysaccharidosis Type I

“…As molecular analysis alone can be an unreliable tool for prediction of disease severity, GAG analysis combined with the use of postanalytical tools can help to determine pathogenicity of those dreaded variants of uncertain clinical significance. A recent publication by Clarke et al [31] discusses the complexity of using genotypic information to predict phenotype in MPS I, with unique genotypes in 12.4% and 40% of patients with severe and attenuated MPS I, phenotypic variability associated with certain missense variants, and inability of current biochemical assessments to predict phenotype. It is also important to note that while the data originated from a voluntary patient registry, 18 patients had only one IDUA variant reported, highlighting the limitations of molecular testing without accompanying biochemical phenotyping as a component of newborn screening.…”

Mucopolysaccharidosis Type I

“…It is quite important, though, in cases with unclear enzyme results and particularly for prenatal diagnosis in affected families. More recently, molecular diagnosis has been recognized as an important part of the diagnostic process, especially since therapeutic options have become available and genotype-phenotype correlations have become clearer [62,63].…”

“…Individuals who are homozygous or compound heterozygotes for these variants have severe phenotype. In 2003, Sanofi-Genzyme (Cambridge, Massachusetts, USA) launched the MPS I Registry (https://clinicaltrials.gov, NCT00144794) to gather retrospective and prospective clinical, biochemical, and genotype information from over 530 individuals with MPS I, which aided in delineating a better genotype-phenotype correlation [63].…”

“…For instance, p.[Pro533Arg];[Pro533Arg] has been seen in seven individuals with severe phenotypes and 17 individuals with the attenuated form. Data from the MPS I Registry show that over 50% of the affected individuals have unique genotypes and several missense variants are associated with multiple phenotypes, making it impossible to predict the phenotype solely based on the genotype information for a vast number of patients [63]. Table 3 describes a summary of genotypes and the number of patients within each of the disease forms reported in the MPS I Registry.…”

Evaluation of Multiple Methods for Quantification of Glycosaminoglycan Biomarkers in Newborn Dried Blood Spots from Patients with Severe and Attenuated Mucopolysaccharidosis-I

“…The rate of below cutoff samples is about 20 per 100,000 newborns using MS/MS [ 1 ]. Many of the hits from MS/MS- and fluorometry-based enzyme analysis are false positives, because of the partial overlap of the reference and affected ranges [ 3 ] and because of the presence of pseudodeficiencies [ 4 ]. This is the typical situation with NBS for lysosomal storage diseases.…”