Undiagnosed Disease Programs and Networks

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1 Undiagnosed Disease Programs and Networks Gareth Baynam Clinical Geneticist, Genetic Services of Western Australia Director, Undiagnosed Diseases Program, WA Head, Western Australian Register of Developmental Anomalies

2 Bill we have a problem

3 Undiagnosed Diseases Program 2008 MISSION: accurate diagnosis To discover new diseases that provide insight into human physiology and genetics MECHANISM: Cross-disciplinary Complementary domain expertise triangulation Centred on one patient, at the same time and in the same place Sharing Human expertise plus technology

4 USA UDP - Outcomes Diagnosis of 25% (40%) of the most complex chronic disorders that have escaped medical diagnosis Reduced the social isolation of the undiagnosed New management protocols. New treatments. Drug repurposing. Supported clinical training and clinical research development. Publicity for medical care and research. Identified new diseases. More than 50 published or in press papers, the majority in high or very high impact journals.

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7 Courtesy Bill Gahl

8 sonal Genomics re Disease) ophila Gene Left ology Arm Back to the GWAS WES Patients WGS WES Gene Trap & AL4 Expression Genes/Variants CRISPR SA 2A polya UDN-MOSC: integration & collaboration WGS SA 2A polya Ortholog Prediction Trojan Exon Cassette HDR Strong Candidates SA GFP SD MiMIC-GFP Cassette Protein Trap SA fc31 Integrase Population Genomics Patients (Common Disease/Traits) Right Homology Arm Personal Genomics (Rare Disease) Application Gene Trap & Model Organisms Screening HDR Sequence Experiments Center (MOSC) GAL4 Expression UAS cdna polya polya SA 2A Experiments SA GFP SD Bioinformatics Pipeline MiMIC-GFP Cassette Public Human Databases Protein Trap RMCE Private Human Databases SA GFP SD Model Organism Databases Phenotypic Characterization Fly Core Rescue Conditional Knockdown (igfpi/degradfp) RMCE Mouse GFP Production SD & PIs: Michael Wangler Phenotypin Shinya g Yamamoto Knockout Mouse Project (KOMP) & IMPC Population Genomics (Common Disease/Traits) Fish Core PIs: Monte Westerfield John Postlethwait Coordination Center (Gateway) GWAS WES WES WGS WGS UAS cdna polya UAS cdna polya Genes/Variants Transgenic Vector Transgenic Vector Human cdna Ortholog attb Human cdna Prediction fc31 Drosophila Gene attb Integrase attp Docking Site fc31 Left Right Reference Integrase Transgenic Fly Homology attp Docking Homology or Variant Site CRISPR Genotype with human & Phenotype cdna Arm Arm Sequence SA 2A polya Reference UAS cdna polya Transgenic Trojan Fly Information Exon Cassette or Variant Rescue with human cdna Over-Expression fc31 Integrase PI: Hugo Bellen Phenotypic Characterization Over-Expression Protein Expression & Localization Analyses Conditional Knockdown (igfpi/degradfp) Canadian UDN Metabolomics Core Protein Expression & Localization Analyses Assignment Clinical Data Sequence Data Clinical Sites (7) DNA Samples Sequencing Cores (2) Whole Exome (WES) Whole Genome (WGS) Large Scale Human Sequencing Efforts

9 MARRVEL.ORG (Model organism Aggregated Resources for Rare Variant ExpLoration)

10 Expansion to a UDN Central NHGRI IRB Formal data sharing agreements Personal information shared within UDN De-identified data with others. First patients: August 2015.

11 Progress Toward Diagnosis Applications 1162 Accepted 459 Evaluated 197 Diagnosed 32 Exomes sent 444 Genomes 366 As of January 2017; UDN opened August 2015

12 Undiagnosed Diseases Network International(UDNI): White Paper for Global Actions to Meet Patient Needs Domenica Taruscio a, Stephen C. Groft b, Helene Cederroth c, Béla Melegh d, Paul Lasko e, Kenjiro Kosaki f, Gareth Baynam g, Alexa McCray h, William A. Gahl i Molecular Genetics and Metabolism 116:223-5, 2015.

13 UDNI Meetings - Rome September Budapest June Vienna February (Perth, WA August 2016) - Tokyo November Stockholm August 2017 Supported by the NIH Common Fund and the Wilhelm Foundation.

14 China

15 UDPs Operating in: - Italy - Australia - Japan - Vienna - Shanghai - Others?

16 Achievements/Collaborations 1.Italy A. USA-Italy letter of collaboration on Rare and Undiagnosed Diseases. B. Italian Ministry of Foreign Affairs funded Undiagnosed rare diseases: A joint Italy- USA project, January C. Telethon Undiagnosed Diseases Program. 2. Japan A. Japanese NIH (AMED) signed MOU with U.S. Office of Science and Technology; includes undiagnosed diseases (Jan 2016). B. Japan set aside $6M for its own UDP (2015).

17 Agreements/Collaboration 3. Western Australia A. Undiagnosed Diseases Conference Aug B. Government sponsored Australian UDP. 4. Vienna A. Obtained Ludwig Boltzmann Institute grant to establish Austrian UDP (2015). 5. Europe: European Union of Medical Specialists created a Multidisciplinary Joint Committee for Rare and Undiagnosed Diseases (2015). 6. Spain, Korea, India, Turkey are forming Programs. Others?

18 The UDNI has: Developed and ratified a Charter Determined criteria for membership (Individual & Institutional) Created policies for governance, a Board of Directors, and voting Formulated & ratified data-sharing policies Involved advocacy groups Established collaborations!

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20 Models Big Small Likely everything in between

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22 Small Learn from the big guys Borrow and adapt Use existing resources and re-shape clinical services Build on existing clinical and advocacy partnerships Low patient numbers and then increase All the time partnering with research, existing and new resources

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25 66 % Est 2015 Centre for Precision Medicine for Children

26 Why UDPs work Aligned to need Patient engagement CROSS-disciplinary Inspiration and invigoration Phenotyping technology

27 What is your PO?

28 Acknowledgements