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

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.

Keywords: Wilson and Jungner criteria; genetics-first; heel prick; inborn errors of metabolism; inherited metabolic disease; newborn screening; next-generation sequencing; treatability.

Figure 1

A discussion-based literature search to select genes associated with IMDs for next-generation sequencing as a first-tier approach in newborn screening. NBS = newborn screening, dark blue = project team + core team, light blue = core team only. References: [26] Kiewiet, G.; Westra, D.; de Boer, E.N.; van Berkel, E.; Hofste, T.G.; van Zweeden, M.; Derks, R.C.; Leijsten, N.F.; Ruiter-kamp-Versteeg, M.H.; Charbon, B.; et al. Future of Dutch NGS-Based Newborn Screening: Exploring the Technical Possibilities and Assessment of a Variant Classification Strategy. Int. J. Neonatal Screen. 2024, 10, 20; [48] Ferreira, C.R.; Rahman, S.; Keller, M.; Zschocke, J.; ICIMD Advisory Group. An international classification of inherited metabolic disorders (ICIMD). J. Inherit. Metab. Dis. 2021, 44, 164. [49] Ferreira, C.R.; Van Karnebeek, C.D.M.; Vockley, J.; Blau, N. A proposed nosology of inborn errors of metabolism. Genet. Med. 2019, 21, 102–106.