BeSolveRD: The Belgian Genome Resource to Resolve Rare Diseases

Despite the diagnostic implementation of chromosomal microarrays and whole exome sequencing (WES) for patients with intellectual disabilities/developmental disorders (ID/DD), over half remain undiagnosed.

Within the BeSolveRD project the Belgian genetic centers engaged in a multicentric, prospective, randomized control trial with the aim to:

  • technically validate whole genome sequencing (WGS) at different genetic centers in Belgium,
  • investigate the clinical utility of WGS for ID/DD diagnosis
  • assess the health economic impact of WGS

In this study, 800 patients and both parents will be recruited of which half will be sequenced by WES and half with WGS. Illumina® engages in providing the consumable cost for a total of 1270 genomes to be sequenced with 40x coverage.

The different Work Packages that make up the BeSolveRD project are:

  • Project Management(WP Leader: Joris Vermeesch (KU Leuven))

  • WP 1: Patient selection(WP Leader Elfride De Baere (UGent))

Patients are considered for inclusion based on the following criteria and if he/she did not previously have any type of NGS testing:

  • ID/DD (moderate to profound)
  • ID/DD (mild to moderate) AND family recurrence AND normal parents
  • ID/DD (mild to moderate) AND dysmorphism (≥3 well documented minor signs)
  • One major malformation AND dysmorphism (≥3 well documented minor signs)
  • Multiple major malformations in 2 or more different organ systems.

AIM: Each center will be recruiting according to standard procedures and the number of patients included will reflect the current ID/DD diagnostic activities in the different centers

  • WP 2: Technical validation(WP Leaders: Wouter Bossuyt (KU Leuven); Björn Menten (UGent))
    • In order to ensure all WGS sequencing programs excel the same specificity and sensitivity thresholds, cross validation has been performed. An inter-laboratory comparison between the different WGS diagnostic protocols was conducted prior to the start of the study.

AIM: Decision on library prep kit(s), methods that can be used for the study

AIM: Thorough technical validation in each sequence Center

  • WP 3: Bioinformatics(WP Leaders: Leonor Palmeira (CHU Liège); Catharina Olsen (VUB); Erika Souche (KU Leuven))
    • The bioinformatics analysis will focus on the detection and annotation of sequence variants (SNVs), Copy Number Variants (CNVs) as a first tier and more complex Structural Variants (SVs) and repeat expansions as a second tier (end of project). Tools aiming at identifying noncoding variants such as splicing events and regulatory variants (e.g. in enhancers) will be evaluated.

AIM: Selection of testing tools , assignment of the different tools to be tested across centers, sharing of test results

AIM: Implementation & validation CNV and SNV detection: best tools in containers (share the different containers across centers

  • WP 4: Data Handling(WP Leaders: Leonor Palmeira (CHU Liège); Amin Ardeshirdavani (KU Leuven); Julie Soblet (ULB))
    • Privacy risks associated with sharing of personal genetic information, and the costs of WGS data storage and transfer could impede the power of WGS in a clinical setting.
    • A federated model of data sharing answers most privacy issues by maintaining the data within each clinical center, and providing an interoperability layer to retrieve population-level information from each center without leaking private genetic information.

AIM: Pilot deployment of a federated database in all genetic centers

AIM: Implementation of data sharing approach chosen by the consortium

  • WP 5: Diagnostic Analytical Validation(Pascale Hilbert (IPG); Kris Van Den Bogaert (KU Leuven))
    • The validated sequencing technology (in WP2) and developed bioinformatics pipelines (in WP3) will be translated into a diagnostic framework for implementation of WGS in the clinic. Pipelines will be tested for accuracy, sensitivity and specificity for different types of variants by comparing WGS analytical results of positive controls with results obtained previously by gold standard techniques for these variants. A WGS working group will be set up within the framework of the BeSHG and the College for Genetics and Rare Diseases, in order to document and regularly revise best practice guidelines on a national level for WGS, including technical as well as clinical aspects.

AIM: Analytically validated clinical grade genome sequencing

AIM: Standardized clinical WGS interpretation and reporting

AIM: National best practice guidelines for clinical WGS

  • WP 6: Clinical Impact(WP Leaders: Aimé Lumaka (CHULiège); Marije Meuwissen (UA); Karin Dahan (IPG); Nicole Revencu (UCL))
    • The present project will study: the clinical validity, including the added diagnostic yield of WGS and the possible shortening of the diagnostic odyssey compared to current standards of care, and the clinical utility that includes any direct or indirect benefit to the patients and their families in terms of guidance for patient management and reproductive options, and the potential implications of WGS-derived secondary findings.

AIM: evaluate the diagnostic yield of WGS as compared to current standard of care, for different types of genetic anomalies as defined in WP1 and WP3

AIM:evaluate the impact of applying WGS on the TAT as compared to our current SoC

AIM: study the clinical utility of WGS

AIM: study the indirect impact of the use of NGS regarding secondary findings

  • WP 7: Health Economic Aspects of WGS(WP Leaders: Erik Schokkaert & Jeroen Luyten (KU Leuven))
    • Make health economic assessment of WGS implementation to support government decision making. Different Health economic aspects will be evaluated. These include: total direct costs from a healthcare payer perspective of different screening strategies, additional direct healthcare costs following different screening strategies as well as broader patient costs and indirect costs of productivity losses in order to calculate a total societal cost of different screening strategies.

AIM: assess the payer cost effectiveness of WGS vs. current SoC

  • WP 8: Implementation in Health Care(WP Leaders: Gert Matthijs (KU Leuven); Elfride De Baere (UGent))

Due to its rapid pace of development, genomic medicine can be disruptive for the system. The introduction of WGS into health care requires a combined initiative of healthcare providers, led by geneticists, and the different governmental departments and agencies.

If proven beneficial, WGS testing will have to be reimbursed by the government. If not, the Belgian system is at risk for diverting to ‘two-speed’ healthcare provisions.

Most important aspects are: The reimbursement of WGS by the healthcare system, Phasing of the introduction of WGS for the different disciplines, Information to all care providers and to the public.

Aim: Work out roadmap to reimbursement of WGS

Aim: Streamline information flows to primary care providers and the public