General introduction

Technological advances in Next Generation Sequencing (NGS) have created considerable excitement in genomics research, in particular in the field of rare genetic disease. Moreover, this technology has started to enter healthcare systems in the Netherlands, and worldwide. As Whole Genome Sequencing (WGS) produces an unprecedented amount of detailed genetic information of an individual, it requires a broad and thorough evaluation to guide and judge the practical application into heath care pathways, including future personalized treatments. It is beyond any doubt, that WGS will bring a paradigm shift: for a genetic diagnosis, geneticists and expert clinicians will no longer need to narrow down the differential clinical diagnosis to request sequencing of a specific gene or sets of genes, but all genetic information will be available at once. The results of this genetic analysis will directly guide the diagnostic patient evaluation, moving towards personalised patient care and treatment.

The main challenge for the introduction of clinical WGS for genome diagnostics of rare disease is not necessarily the technology itself, but predominantly the integration of clinical expertise and relevant stakeholders information (e.g. patients, families, clinicians, health care providers, HTA agencies, politics), and as such, requires a systematic assessment of its clinical utility.

Dutch collaboration and dissemination

The research described will be performed by a dutch consortium (RADICON-NL). This consortium consists of 8 academic genetic centers, 2 non academic Neonatal intenisve care units (NICU’s) and several patient organisations.

The Radicon-NL consortium is embedded in many other national and international networks. In this way the results can be broadly disseminated.
The consortium contains experts from different areas of expertise: technical know how (WGS and genetic testing), medical know how (pedeatricians, genetic counselors) and experts who can perform health technology assessments (HTA’s) are combined in the project with datamanagement experts and patient organisation that can disseminate the results to the patients and the public.

Project objectives

The goal of the ZonMw “WGS first approach”project is to determine the added value of Whole Genome Sequencing (WGS) as a first tier genetic test in the care pathway of patients with a rare genetic disease.
The hypothesis is that a ‘one-test-fits-all’ WGS approach as a first tier genetic diagnostic test increases the diagnostic yield in a shortened time frame, and reduces the complexity and costs associated with obtaining this diagnosis. This approach will result in early access to personalized patient care, reducing co-morbidity and mortality.
The aim of this project is to perform a clinical utility study and assess not only the ability of the diagnostic test to ameliorate diagnostic yield, but also to address cost-effectiveness, the patients’ perspectives, and evaluate the ethical and psychological impact on patients and their families.
Thus the overall ambition of this project is to assess the expected improvement of the diagnostic yield for rare disease using a single WGS test at the start of the diagnostic tract resulting in a shortened time-to-diagnosis while reducing the costs-to-diagnosis, and increasing the potential to influence the clinical decision making process eventually enabling precision medicine.
We decided to use two model disorders: neurodevelopmental disorders (NDD) and neonates presenting at the neonatal intensive care unit (NICU) with a disorder of presumed genetic origin. For both model diseases, the genetic and clinical heterogeneity warrant a genome-wide genetic approach to identify the genetic origin. In addition, for NDD the standard diagnostic tract is lengthy and involves many (invasive) diagnostic procedures, and, a proof-of-concept study using WGS has shown the potential of WGS as first tier test. For the NICU the genetic diagnostic yield in the standard care is low as turn-around-times of current genetic testing are too long to be able to impact clinical decision-making. Yet, the first reports on rapid genetic testing in NICU patients have shown to have a beneficial effect on diagnostic yield. Combining these two model disorders will as such provide insight into two ends of the spectrum: NDD involving many sequential tests in which genetic testing accounts for up to 40% of cost-to-diagnosis9 with limited treatment options, and rare disorders at the NICU where limited genetic testing is possible (i.e. low genetic costs), but where timing is of essence to impact clinical decision making and a large amount of money is spent on intensive care treatment(s) that at the end turned out to be futile, because of an underlying genetic disorder that implies a poor prognosis. For the latter, offering ‘rapid genetic testing’ is of utmost importance, which takes our clinical utility study of the ‘WGS-first approach’ to the next level, as we are not only assessing the utility of WGS, but also when performed as rapid genetic test. Assessing the clinical utility of WGS also merits analysis of other prerequisites for large-scale implementation as well as to survey patients expectations and needs. We have therefore determined the following aims to address these different aspects of clinical utility using NDD and NICU as model disorders for rare disease:
AIM 1: To prospectively evaluate the clinical utility of a WGS as the first clinical diagnostic approach, including the assessment of diagnostic yield, cost-effectiveness, the impact on medical decision making, and budget impact of WGS on the Dutch healthcare system for NDD and NICU patients as model disorders for rare genetic disease.

  • AIM 2: To develop best practice guidelines defining a standardized format for WGS analysis, interpretation and reporting, in a ‘WGS-first clinical setting’.
  • AIM 3: To facilitate an (inter)national platform for sharing of WGS data, providing an essential knowledge base for the diagnostic interpretation of WGS data in a clinical setting.
  • AIM 4: To develop a counselling support and patient empowerment framework (CSPEF).
  • AIM 5: To investigate the merits and burdens of a WGS-first approach as the parents experience them and assess how parents evaluate the outcome of the WGS-first approach
  • AIM 6: To disseminate the results of RADICON-NL

Whole genome sequencing (WGS)

Whole Genome Sequencing: Determining the complete DNA sequence of an individual to identify the cause of disease.

Neurodevelopmental disorders (NDD) & Neonatal intensive care unit (NICU)

Schematic representation of two model disorders and the health care resource use as function over time. The blue line represents the anticipated standard care pathway which needs to be confirmed by a retrospective analysis in WP1. The orange dotted line represents our anticipated result of the WGSfirst approach, with the orange star indicating the inclusion of the patients in our parallel study. In addition, the schematic representation illustrates the differences between the two model disorders. That is, NICU patients have a lower ‘volume of diagnostic testing’ when starting the diagnostic quest, but may have an impact on clinical decision making (yellow) if the WGS-first approach delivers results instantly (black dotted horizontal lines). NDD has less treatment options, and thus the impact on clinical management may be more limited. The results of a WGS-first approach may be obtained in a ‘less time sensitive’ manner.