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Towards Next Generation Sequencing (NGS)-based newborn screening: a technical approach/study to prepare challenges ahead.


Onderzoek naar nieuwe DNA technologie binnen de neonatale hielprikscreening


Binnen de neonatale hielprikscreening (NHS) zijn biochemische testen nu de eerste test en wordt DNA onderzoek vaak gebruikt voor bevestiging omdat de meeste met NHS opgespoorde aandoeningen erfelijk zijn. Door de verbeterde DNA-technologie wordt het in de toekomst wellicht mogelijk om DNA testen als eerste test te gebruiken. DNA testen kunnen gericht zijn op een klein deel van het DNA, of breed zijn waarbij het hele exome (WES) of hele genoom (WGS) bepaald wordt. Naast kansen kennen DNA testen ook beperkingen bij de inzet in de NHS. De vertaalslag van DNA-data naar het risico op een aandoening is namelijk vaak complex.

Onderzoek en verwachte uitkomst

In het huidige project “NGSf4NBS” wordt eerst gekeken voor welke stofwisselingsziekten (SZ) een DNA test als eerste NHS stap geschikt kan zijn. Daarna zal een pijplijn ontwikkeld worden om SZ met een gerichte DNA test, WES of WGS op te sporen. Tot slot zal voor enkele SZ onderzocht worden of deze pijplijn succesvol geïmplementeerd kan worden in een NHS-laboratorium.

Meer over pre- en neonatale screening


Samenvatting van de aanvraag

Newborn blood screening (NBS) aims to identify newborns in which immediate treatment saves life or improves outcome. To date, NBS is performed analyzing dried blood spots (DBS) on filter paper for abnormal metabolite concentrations. Multiple next generation sequencing (NGS) techniques to expand and improve present NBS are now available and they can be applied using a single 3.2 mm punch from a DBS. NGS-first techniques for NBS (NGSf4NBS) allow identification of diseases lacking reliable biochemical footprints in DBS, may decrease the number of false positives and negatives, as recognized by the Dutch Health Council in 2015, and may ultimately antedate diagnosis of diseases that can be found by NGS. Theoretical reviews and pilot studies explored possibilities and challenges of genomic analysis in NBS, while our recent pilots showed feasibility of NGS analysis for many genes. While the results of these reviews and studies show a promising future, the actual step of applying NGS analysis in a more or less routine fashion in the screening laboratory has not been taken. It is the aim of this project to make exactly that next step possible taking inborn errors of metabolism (IEM) as example. Here, we propose the following objectives: 1) To identify a list of IEM eligible for NGS-first testing in NBS by inviting IEM and non-IEM colleagues to increase the list of potential IEM and make colleagues in other pediatric fields aware of NGS-first possibilities and challenges (WP1); 2) To develop a rapid NGS based workflow (including analytical and bio-informatic pipeline)(WP2); 3) To prepare for incorporation of this pipeline in our NBS program (WP3). These objectives are elaborated in the following six basic task statements performed in 3 workpackages (WP): 1) Identify relevant IEMs meeting the existing criteria for NBS using an evidence and consensus based approach (WP1), 2) identify all the corresponding disease causing genes and reported variants in the encoding genes related to these to define a specific NBS IEM gene panel (WP1), 3) study to what extent NGS could complement and extend current screening protocols (WP2), 4) establish feasibility, its limitations, and execute a systematic comparison of different technical approaches for speed, robustness, specificity and costs to establish best-practices and quality standards (WP2), 5) propose reporting and action plans for positive NGS-test results (WP3), 6) offer insights in the practical and financial consequences of the implementation of genomic-first in the NBS program (WP3). This project will provide for a project leader, technical assistance, data management and planning assistance, bio-informatics assistance and benchfee, first to make an inventory of diseases and conditions eligible for a NGS4NBS approach (working from UMCG and RadboudUMC facilities and later from the NBS reference laboratory of the RIVM), secondly to generate the necessary knowledge for a full functional analytical and bio-informatics pipeline at the UMCG and RadboudUMC localities, and thirdly to transfer this pipeline to the RIVM reference laboratory for NBS. Here, this pipeline will be applied in proof-of-principle experiments, showing for the first time that NGS-first-analysis in NBS is feasible and advantageous. With the joint forces of all relevant stakeholders, NGS4fNBS may work towards the first initiatives for the application of NGS in routine Dutch NBS in the future. Our team holds the top IEM-specialists, two top clinical genetic departments and the program management and reference laboratory of the Dutch neonatal screening program. The team has relevant links with the United for Metabolic Disease (UMD) initiative, enabling exchange of knowledge to keep the project in line with the demands of the clinical management of IEM and swift exchange of relevant knowledge. The Dutch NBS is firmly grounded through the application of the Wilson and Jungner criteria and deals with strict demands concerning ethical, legal and social implications, one of which is its social acceptability, and another the relevance of the disease. Two major organisations representing patients with genetic disorders and, more specifically, IEM (i.e. the Organization for parents and patients with metabolic disease (VKS) and Dutch Patient Alliance for rare and Genetic diseases (VSOP)- and the Dutch National Heredity Information Center (Erfocentrum) support this project and are committed to collaborate in one of the work packages or the steering committee for this project. NGSf4NBS is a technical project dealing with analytical feasibility of new techniques in a, with respect to NBS, revolutionary fashion that perfectly fits the present call of The Netherlands Organisation for Health Research and Development (ZonMw). NGSf4NBS will work towards a workflow for a dedicated NGS-first NBS infrastructure that ultimately enables downstream implementation in the Dutch NBS system in the foreseeable future (5-10 years).


Looptijd: 100%
Looptijd: 100 %
Onderdeel van programma:
Gerelateerde subsidieronde:
Projectleider en penvoerder:
Prof. dr. F.J. van Spronsen
Verantwoordelijke organisatie:
Universitair Medisch Centrum Groningen