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

Dawn Peck ,Brianna K Murray,Silvia Tortorelli,Linda Spencer,Ayesha Ahmad,Kelly L Jones,Jean M Lacey,Sarah Viall,Devin Oglesbee,Piero Rinaldo,Dimitar Gavrilov,Dietrich Matern,Amy Siemon,Kimiyo Raymond,Rachel Fisher,J Austin Hamm,Gisele Pino,Natalie Shallow,Amy White ,April Studinski

doi:10.3390/ijns6010010

Abstract

Enzyme-based newborn screening for Mucopolysaccharidosis type I (MPS I) has a high false-positive rate due to the prevalence of pseudodeficiency alleles, often resulting in unnecessary and costly follow up. The glycosaminoglycans (GAGs), dermatan sulfate (DS) and heparan sulfate (HS) are both substrates for α-l-iduronidase (IDUA). These GAGs are elevated in patients with MPS I and have been shown to be promising biomarkers for both primary and second-tier testing. Since February 2016, we have measured DS and HS in 1213 specimens submitted on infants at risk for MPS I based on newborn screening. Molecular correlation was available for 157 of the tested cases. Samples from infants with MPS I confirmed by IDUA molecular analysis all had significantly elevated levels of DS and HS compared to those with confirmed pseudodeficiency and/or heterozygosity. Analysis of our testing population and correlation with molecular results identified few discrepant outcomes and uncovered no evidence of false-negative cases. We have demonstrated that blood spot GAGs analysis accurately discriminates between patients with confirmed MPS I and false-positive cases due to pseudodeficiency or heterozygosity and increases the specificity of newborn screening for MPS I.

Highlights

Interest in newborn screening for Mucopolysaccharidosis type I (MPS I) has increased following the development of dried blood spot screening assays [1], availability of effective treatments [2,3], and increasing evidence that early intervention improves patient outcomes [4]
Thirty seven cases were compound heterozygous for a pathogenic variant or variant of unknown significance (VUS) and a pseudodeficiency or wild-type allele, suggestive of carrier status
Our findings suggest that second-tier GAGs testing and postanalytical interpretation has several important benefits compared to molecular testing, such as avoidance of unnecessary patient recall, decreased assay cost and turnaround time, the prevention of identification of pseudodeficiency, carriers, and cases with inconclusive molecular results which may receive unnecessary clinical follow up, as well the provision of an actual biochemical phenotype of GAGs metabolism

Summary

Introduction

Interest in newborn screening for Mucopolysaccharidosis type I (MPS I) has increased following the development of dried blood spot screening assays [1], availability of effective treatments [2,3], and increasing evidence that early intervention improves patient outcomes [4]. Numerous pilot and full-population screening programs using measurement of α-l-iduronidase (IDUA) activity have been underway in several countries and US states—many of which have experienced a high false-positive rate due to the overlap of IDUA activity between unaffected and affected patients and a high incidence of pseudodeficiency alleles in IDUA, resulting in overall poor specificity for MPS I [5,6,7]. While several programs have implemented second-tier molecular testing in an attempt to address the poor specificity of enzymatic screening alone, this approach has proved to be problematic due to the discovery of private mutations, variants of unknown significance, identification of carrier status and limitations of utilized methodology [8,9]. Pseudodeficiency for IDUA was first reported in 1985 [11], and was thought to be a rare occurrence prior to newborn screening

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Conclusion