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. 2020 Feb 7;6(1):10.
doi: 10.3390/ijns6010010. eCollection 2020 Mar.

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

Dawn S Peck  1 , Jean M Lacey  1 , Amy L White  1 , Gisele Pino  1 , April L Studinski  1 , Rachel Fisher  2 , Ayesha Ahmad  2 , Linda Spencer  3 , Sarah Viall  4 , Natalie Shallow  5 , Amy Siemon  6 , J Austin Hamm  7 , Brianna K Murray  8 , Kelly L Jones  8 , Dimitar Gavrilov  1 , Devin Oglesbee  1 , Kimiyo Raymond  1 , Dietrich Matern  1 , Piero Rinaldo  1 , Silvia Tortorelli  1
Affiliations

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

Dawn S Peck et al. Int J Neonatal Screen. .

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.

Keywords: GAGs; MPS I; biomarkers; newborn screening; postanalytical interpretation; second-tier testing.

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Conflict of interest statement

Conflicts of InterestThe authors declare no conflict of interest.

Figures

Figure 1
Figure 1
CLIR dual scatter plot; calculated to help determine the differential diagnosis between low IDUA activity more likely being true positive due to MPS I vs. false positive due to pseudo deficiency or IDUA carrier status. (A) Distribution of scores of cases (MPS I (blue dots) n = 10; false positives (purple circles) n = 67) confirmed by genotyping; (B) Distribution of scores of 7 cases with two variants in trans and at least one variant of uncertain significance (VUS; either pathogenic/VUS and VUS/VUS) and one case with no genotype.
Figure 2
Figure 2
(A) Dermatan (DS) and heparan (HS) sulfate values of group 3 cases (red dots) are plotted against the reference population (green bands) (DS n = 3113; HS n = 3165). (B) IDUA genotypes of cases with higher levels of both DS and HS. (C) IDUA genotypes of cases with lower levels of DS and HS. path: pathogenic variant; likely path: likely pathogenic variant; VUS: variant of unknown significance; pseudo: pseudo deficiency allele; wt: wild type.
See this image and copyright information in PMC

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