Newborn Screening by DNA-First: Systematic Evaluation of the Eligibility of Inherited Metabolic Disorders Based on Treatability

Overview

Journal Int J Neonatal Screen

Date 2025 Jan 23

PMID 39846587

Authors

Abigail Veldman

Birgit Sikkema-Raddatz

Terry G J Derks

Clara D M van Karnebeek

M B Gea Kiewiet

Margaretha F Mulder

Marcel R Nelen

M Estela Rubio-Gozalbo

Richard J Sinke

Monique G de Sain-van der Velden

Gepke Visser

Maaike C de Vries

Dineke Westra

Monique Williams

Ron A Wevers

M Rebecca Heiner-Fokkema

Francjan J van Spronsen

Affiliations

Soon will be listed here.

Abstract

The biomarker-based Dutch Newborn Screening (NBS) panel (as of 2024) comprises 19 inherited metabolic disorders (IMDs). With the use of next-generation sequencing (NGS) as a first-tier screen, NBS could expand to include IMDs that lack a reliable biochemical footprint in dried blood spots, while also reducing secondary findings. To be eligible for inclusion in NBS, an IMD needs to fulfill the Wilson and Jungner criteria, with treatability being one of the most important criteria. In this study, we aimed to identify IMDs eligible for DNA-first NBS when considering only treatability in the context of NBS as a prerequisite. First, three independent reviewers performed a systematic literature review of the 1459 genotypic IMDs and their causative gene(s), as described in the International Classification of Inherited Metabolic Disorders (dated 1 February 2021), applying 16 criteria to exclude non-treatable disorders. Eligible disorders were then discussed in three online meetings with a project group of clinical laboratory geneticists, medical laboratory specialists specialized in IMD, and pediatricians with expertise in IMDs. Based on treatability, we identified 100 genes, causing 95 IMDs, as eligible for NBS, including 42 causal genes for the IMDs in the current biomarker-based NBS. The other 58 genes are primarily associated with treatable defects in amino acid metabolism and fatty acid oxidation. Other IMDs were excluded, most often because of insufficient literature. As the evaluation of treatability was not straightforward, we recommend the development of standardized treatability scores for the inclusion of IMDs in NBS.

References

Milko L, Berg J . Age-Based Genomic Screening during Childhood: Ethical and Practical Considerations in Public Health Genomics Implementation. Int J Neonatal Screen. 2023; 9(3). PMC: 10366892. DOI: 10.3390/ijns9030036. View

Sturdy S, Miller F, Hogarth S, Armstrong N, Chakraborty P, Cressman C . Half a Century of Wilson & Jungner: Reflections on the Governance of Population Screening. Wellcome Open Res. 2020; 5:158. PMC: 7468564. DOI: 10.12688/wellcomeopenres.16057.2. View

Kemper A, Green N, Calonge N, Lam W, Comeau A, Goldenberg A . Decision-making process for conditions nominated to the recommended uniform screening panel: statement of the US Department of Health and Human Services Secretary's Advisory Committee on Heritable Disorders in Newborns and Children. Genet Med. 2013; 16(2):183-7. DOI: 10.1038/gim.2013.98. View

Yang H, Al-Hertani W, Cyr D, Laframboise R, Parizeault G, Wang S . Hypersuccinylacetonaemia and normal liver function in maleylacetoacetate isomerase deficiency. J Med Genet. 2016; 54(4):241-247. DOI: 10.1136/jmedgenet-2016-104289. View

Kiewiet G, Westra D, de Boer E, van Berkel E, Hofste T, van Zweeden M . Future of Dutch NGS-Based Newborn Screening: Exploring the Technical Possibilities and Assessment of a Variant Classification Strategy. Int J Neonatal Screen. 2024; 10(1). PMC: 10971161. DOI: 10.3390/ijns10010020. View

Kelly N, Makarem D, Wasserstein M . Screening of Newborns for Disorders with High Benefit-Risk Ratios Should Be Mandatory. J Law Med Ethics. 2016; 44(2):231-40. PMC: 5381153. DOI: 10.1177/1073110516654133. View

la Marca G, Carling R, Moat S, Yahyaoui R, Ranieri E, Bonham J . Current State and Innovations in Newborn Screening: Continuing to Do Good and Avoid Harm. Int J Neonatal Screen. 2023; 9(1). PMC: 10057559. DOI: 10.3390/ijns9010015. View

Ferreira C, Rahman S, Keller M, Zschocke J . An international classification of inherited metabolic disorders (ICIMD). J Inherit Metab Dis. 2020; 44(1):164-177. PMC: 9021760. DOI: 10.1002/jimd.12348. View

Cavicchi C, Oussalah A, Falliano S, Ferri L, Gozzini A, Gasperini S . PRDX1 gene-related epi-cblC disease is a common type of inborn error of cobalamin metabolism with mono- or bi-allelic MMACHC epimutations. Clin Epigenetics. 2021; 13(1):137. PMC: 8254308. DOI: 10.1186/s13148-021-01117-2. View

10.

Jennions E, Hedberg-Oldfors C, Berglund A, Kollberg G, Tornhage C, A Eklund E . TANGO2 deficiency as a cause of neurodevelopmental delay with indirect effects on mitochondrial energy metabolism. J Inherit Metab Dis. 2019; 42(5):898-908. DOI: 10.1002/jimd.12149. View

11.

Strand J, Gul K, Erichsen H, Lundman E, Berge M, Tromborg A . Second-Tier Next Generation Sequencing Integrated in Nationwide Newborn Screening Provides Rapid Molecular Diagnostics of Severe Combined Immunodeficiency. Front Immunol. 2020; 11:1417. PMC: 7381310. DOI: 10.3389/fimmu.2020.01417. View

12.

Hagemeijer M, Oussoren E, Ruijter G, Onkenhout W, Huidekoper H, Ebberink M . Abnormal VLCADD newborn screening resembling MADD in four neonates with decreased riboflavin levels and VLCAD activity. JIMD Rep. 2021; 61(1):12-18. PMC: 8411102. DOI: 10.1002/jmd2.12223. View

13.

. Newborn screening: toward a uniform screening panel and system--executive summary. Pediatrics. 2006; 117(5 Pt 2):S296-307. DOI: 10.1542/peds.2005-2633I. View

14.

Chan T, Mak C, Yeung M, Law E, Cheung J, Wong T . Harnessing Next-Generation Sequencing as a Timely and Accurate Second-Tier Screening Test for Newborn Screening of Inborn Errors of Metabolism. Int J Neonatal Screen. 2024; 10(1). PMC: 10971432. DOI: 10.3390/ijns10010019. View

15.

Willemsen M, Verbeek M, Kamsteeg E, de Rijk-van Andel J, Aeby A, Blau N . Tyrosine hydroxylase deficiency: a treatable disorder of brain catecholamine biosynthesis. Brain. 2010; 133(Pt 6):1810-22. DOI: 10.1093/brain/awq087. View

16.

Holm I, Agrawal P, Ceyhan-Birsoy O, Christensen K, Fayer S, Frankel L . The BabySeq project: implementing genomic sequencing in newborns. BMC Pediatr. 2018; 18(1):225. PMC: 6038274. DOI: 10.1186/s12887-018-1200-1. View

17.

Zaidman C, Crockett C, Wedge E, Tabatabai G, Goedeker N . Newborn Screening for Spinal Muscular Atrophy: Variations in Practice and Early Management of Infants with Spinal Muscular Atrophy in the United States. Int J Neonatal Screen. 2024; 10(3). PMC: 11348092. DOI: 10.3390/ijns10030058. View

18.

Burlina A, Jones S, Chakrapani A, Church H, Heales S, Wu T . A New Approach to Objectively Evaluate Inherited Metabolic Diseases for Inclusion on Newborn Screening Programmes. Int J Neonatal Screen. 2022; 8(2). PMC: 9036245. DOI: 10.3390/ijns8020025. View

19.

Adhikari A, Gallagher R, Wang Y, Currier R, Amatuni G, Bassaganyas L . The role of exome sequencing in newborn screening for inborn errors of metabolism. Nat Med. 2020; 26(9):1392-1397. PMC: 8800147. DOI: 10.1038/s41591-020-0966-5. View

20.

Spiekerkoetter U, Bick D, Scott R, Hopkins H, Krones T, Gross E . Genomic newborn screening: Are we entering a new era of screening?. J Inherit Metab Dis. 2023; 46(5):778-795. DOI: 10.1002/jimd.12650. View