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Two-Tiered Newborn Screening with Post-Analytical Tools for Pompe Disease and Mucopolysaccharidosis Type I Results in Performance Improvement and Future Direction
Open AccessArticle

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

1
Biochemical Genetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA
2
Division of Pediatric Genetics, Metabolism and Genomic Medicine, Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA
3
Division of Genetic, Genomic and Metabolic Disorders, Children’s Hospital of Michigan, Detroit, MI 48201, USA
4
Rare Disease Institute, Children’s National Health System, Washington, DC 20010, USA
5
Division of Medical Genetics and Genomic Medicine, Monroe Carell Jr. Children’s Hospital at Vanderbilt, Nashville, TN 37232, USA
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Division of Genetic and Genomic Medicine, Nationwide Children’s Hospital, Columbus, OH 43205, USA
7
Pediatric Genetics, East Tennessee Children’s Hospital, Knoxville, TN 37916, USA
8
Division of Medical Genetics and Metabolism, Children’s Hospital of the King’s Daughters, Norfolk, VA 23507, USA
*
Authors to whom correspondence should be addressed.
Int. J. Neonatal Screen. 2020, 6(1), 10; https://doi.org/10.3390/ijns6010010
Received: 7 January 2020 / Revised: 30 January 2020 / Accepted: 5 February 2020 / Published: 7 February 2020
(This article belongs to the Special Issue CLIR Applications for Newborn Screening)
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: newborn screening; MPS I; second-tier testing; GAGs; biomarkers; postanalytical interpretation newborn screening; MPS I; second-tier testing; GAGs; biomarkers; postanalytical interpretation
MDPI and ACS Style

Peck, D.S.; Lacey, J.M.; White, A.L.; Pino, G.; Studinski, A.L.; Fisher, R.; Ahmad, A.; Spencer, L.; Viall, S.; Shallow, N.; Siemon, A.; Hamm, J.A.; Murray, B.K.; Jones, K.L.; Gavrilov, D.; Oglesbee, D.; Raymond, K.; Matern, D.; Rinaldo, P.; Tortorelli, S. Incorporation of Second-Tier Biomarker Testing Improves the Specificity of Newborn Screening for Mucopolysaccharidosis Type I. Int. J. Neonatal Screen. 2020, 6, 10.

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