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. 2022 Feb 24;8(1):17.
doi: 10.3390/ijns8010017.

Towards Next-Generation Sequencing (NGS)-Based Newborn Screening: A Technical Study to Prepare for the Challenges Ahead

Abigail Veldman  1 , Mensiena B G Kiewiet  1   2 , Margaretha Rebecca Heiner-Fokkema  3 , Marcel R Nelen  4 , Richard J Sinke  2 , Birgit Sikkema-Raddatz  2 , Els Voorhoeve  5 , Dineke Westra  4 , Martijn E T Dollé  5 , Peter C J I Schielen  6 , Francjan J van Spronsen  1
Affiliations

Towards Next-Generation Sequencing (NGS)-Based Newborn Screening: A Technical Study to Prepare for the Challenges Ahead

Abigail Veldman et al. Int J Neonatal Screen. .

Abstract

Newborn screening (NBS) aims to identify neonates with severe conditions for whom immediate treatment is required. Currently, a biochemistry-first approach is used to identify these disorders, which are predominantly inherited meta1bolic disorders (IMD). Next-generation sequencing (NGS) is expected to have some advantages over the current approach, for example the ability to detect IMDs that meet all screening criteria but lack an identifiable biochemical footprint. We have now designed a technical study to explore the use of NGS techniques as a first-tier approach in NBS. Here, we describe the aim and set-up of the NGS-first for the NBS (NGSf4NBS) project, which will proceed in three steps. In Step 1, we will identify IMDs eligible for NGS-first testing, based on treatability. In Step 2, we will investigate the feasibility, limitations and comparability of different technical NGS approaches and analysis workflows for NBS, eventually aiming to develop a rapid NGS-based workflow. Finally, in Step 3, we will prepare for the incorporation of this workflow into the existing Dutch NBS program and propose a protocol for referral of a child after a positive NGS test result. The results of this study will be the basis for an additional analytical route within NBS that will be further studied for its applicability within the NBS program, e.g., regarding the ethical, legal, financial and social implications.

Keywords: dried blood spot; first-tier; heel prick; inborn errors of metabolism; inherited metabolic disorders; newborn screening; next-generation sequencing.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Overview of the study set-up. IMD = inherited metabolic disorder, NGS = next-generation sequencing, DBS = dried blood spot, WES/WGS: whole exome sequencing/whole genome sequencing.
Figure 2
Figure 2
Preliminary flowchart of the selection process of Step 1.
Figure 3
Figure 3
Estimated turn-around-time from NGS to result. DBS = dried blood spot, QC = quality control, PCR = polymerase chain reaction.
See this image and copyright information in PMC

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