The new EU project for solving the unsolved

1. SOLVE-RD. THE NEW EU PROJECT FOR
SOLVING THE UNSOLVED
Holm Graessn er, Un iversitätskl in iku m
Tü b in gen

2. 2
Learning objectives
(1) Obtain an overview of Solve-RD.
(2) Understand which different cohorts will be investigated by
which approach.
(3) Understand data sharing objectives and policy of Solve-RD.
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3. 3
Issues addressed through Solve-RD
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• 50% of RD patients without confirmed molecular
diagnosis
• Utilising novel European Reference Networks
• Heterogeneous quality in genetic diagnostic and
research labs
• Knowledge and data silos
• Availability of novel omics methodologies that might
help to find a diagnosis
• “Unsolvable syndromes” and ultra-rare diseases

4. 1. Unsolved cases
Definition: unsolved RD case with an inconclusive exome
Number: at least 19.000 cases from ERNs and beyond
Main activities: standardized collation and re-analysis
Rationale:
• Variants that have not been found in the exome are likely
in the exome
• Need big numbers to boost up quality of re-analysis and
meta-analysis

5. Data sharing

6. 2. SPECIFIC ERN COHORTS
Definition: Disease groups specific cohorts from four core ERNs
Numbers:
• 2.000 cases WGS for to achieve a more complete (non-) coding sequence
& SVs etc.
• Smartly chosen phenotypes:
 500 cases with long-read WGS
 >2.000 cases novel omics approaches
Main activities: „beyond the exome“ approaches

7. Genome
Transcriptome
Epigenome
Metabolome/
Proteome
Cellular/
molecular
phenotypes Exome

8. 3. ULTRA-RARE RD
Definition: phenotypically most special/remarkable patients
with RD without an exome
Number: 800
Main activities: Phenotype jamborees and exome

9. Ultra-rare Cases: CPMS platform

10. 4. THE UNSOLVABLES
4. THE UNSOLVABLES
Definition: Highly recognizable clinically defined
diseases/syndromes for which no disease gene was identified
yet (despite WES/WGS)
Number: 120
Main activities: All –OMICS tools to ‘crack’ the “Unsolvables”

11. 4 main cohorts
What are “The Unsolvables”?
ITHACA:
• Hallermann-Streiff syndrome
• Aicardi syndrome
• Gomez-Lopez Hernandez syndrome
• VACTERL
• Etc…
ERN-NMD:
• Oculopharyngodistal myopathy (OPDM)
ERN-RND:
• Familial facial palsie

12. Solving the unsolved Rare Diseases
Coordinators: Olaf Riess, Holm Graessner (Tübingen)
Co-coordinators: Han Brunner (Nijmegen), Anthony Brookes (Leicester)

13. Resources and infrastructures
Core group of 4 European Reference Networks: ERN-RND,
ERN-EURO-NMD, ERN-ITHACA, ERN-GENTURIS
Associated networks: 6 additional ERNs, 2 Undiagnosed Patient
Programmes (Italy, Spain), Genetic Epilesy Network
Existing RD infrastructures: RD-Connect/ELIXIR, Orphanet,
HPO, EuroGentest, Canadian Models and Mechanisms Network
Patient organisations: EURORDIS, Genetic Alliance UK

14. 6 work packages
WP6 COORDINATION AND MANAGEMENT

15. 7 implementation steps

16. Data analysis

17. Biobank
Sequencing
Combined
genome-
phenome
database
Online
analysis
Sample
RD-Connect
Platform
Phenotypic
record
Diagnosis
RD
patient
Clinician/
researcher
Novel challenge: X-omics!
Multi-
omics
data

18. Data sharing

19. Data Sharing
Most important points of Solve-RD data sharing policy
• All exome/genome and phenotypic data that will be collated in Solve-RD
will be submitted to the RD-Connect Genome-Phenome Analysis Platform
(GPAP)
• The RD-Connect Genome-Phenome Analysis Platform complies with the
General Data Protection Regulation, GDPR (Regulation (EU) 2016/679)
• Options for uploading datasets include single dataset upload and bulk
upload
• Specific data access stipulations for Solve-RD in GPAP:
o All data submitters will be able to see which other users of the GPAP have
accessed their submitted datasets and when
o If justified Solve-RD data submitters can define longer embargo periods
before data become accessible to other users of the RD-Connect Genome-
Phenome Analysis Platform

20. Thank you !