Provision of a molecularly confirmed diagnosis in a timely manner for children and adults with rare genetic diseases shortens their "diagnostic odyssey," improves disease management, and fosters genetic counseling with respect to recurrence risks while assuring reproductive choices. In a general clinical genetics setting, the current diagnostic rate is approximately 50%, but for those who do not receive a molecular diagnosis after the initial genetics evaluation, that rate is much lower. Diagnostic success for these more challenging affected individuals depends to a large extent on progress in the discovery of genes associated with, and mechanisms underlying, rare diseases. Thus, continued research is required for moving toward a more complete catalog of disease-related genes and variants. The International Rare Diseases Research Consortium (IRDiRC) was established in 2011 to bring together researchers and organizations invested in rare disease research to develop a means of achieving molecular diagnosis for all rare diseases. Here, we review the current and future bottlenecks to gene discovery and suggest strategies for enabling progress in this regard. Each successful discovery will define potential diagnostic, preventive, and therapeutic opportunities for the corresponding rare disease, enabling precision medicine for this patient population.

Broad Institute of MIT and Harvard Cambridge MA 02142 USA

Center for Human Genetics University of Leuven 3000 Leuven Belgium

Centre for Genomic Sciences University of Hong Kong Hong Kong China

Centre Nacional d'Anàlisi Genòmica Center for Genomic Regulation Barcelona Institute of Science and Technology Universitat Pompeu Fabra 08028 Barcelona Spain

Centre of Genomics and Policy Department of Human Genetics Faculty of Medicine McGill University Montreal QC H3A 1A4 Canada

Children's Hospital of Eastern Ontario Research Institute University of Ottawa Ottawa ON K1H 8L1 Canada

Department of Biology and Medical Genetics 2nd Faculty of Medicine Charles University and University Hospital Motol 150 06 Prague 5 Czech Republic

Department of Computer Science University of Toronto Toronto M5S 1A1 Canada

Department of Genetics King Faisal Research Center Riyadh 11211 Saudi Arabia; Saudi Human Genome Program King Abdulaziz City for Science and Technology Riyadh 11442 Saudi Arabia

Department of Genetics University of Leicester Leicester LE1 7RH UK

Department of Human Genetics Radboud University Medical Center 6525 GA Nijmegen the Netherlands; Maastricht University Medical Center Department of Clinical Genetics 6229 GT Maastricht the Netherlands

Department of Pediatrics University of Washington Seattle WA 98195 USA

Department of Pediatrics University of Washington Seattle WA 98195 USA; Division of Genetic Medicine Seattle Children's Hospital Seattle WA 98105 USA

Department of Social Medicine and Public Health Faculty of Public Health Medical University of Plovdiv Plovdiv 4002 Bulgaria

Departments of Human Genetics and Clinical Genetics Leiden University Medical Center Albinusdreef 2 2333 ZA Leiden the Netherlands

Experimental Division Sidra Medical and Research Center PO Box 26999 Doha Qatar; Genetics Unit Dexeus Woman's Health 08028 Barcelona Spain

Genetic Services of Western Australia Perth WA 6008 Australia

Genomic Medicine Group Galician Foundation of Genomic Medicine and University of Santiago de Compostela 15782 Santiago de Compostela Spain

Institut für Medizinische Genetik und Humangenetik Charité Universitätsmdizin Berlin 13353 Berlin Germany; Jackson Laboratory for Genomic Medicine Farmington CT 06032 USA

John Walton Muscular Dystrophy Research Centre MRC Centre for Neuromuscular Diseases Institute of Genetic Medicine Newcastle University Newcastle upon Tyne NE1 3BZ UK

Lysogene 92 200 Neuilly sur Seine France

McKusick Nathans Institute of Genetic Medicine Johns Hopkins University School of Medicine Baltimore MD 21286 USA

Michael Smith Laboratories Department of Medical Genetics University of British Columbia Vancouver BC V6T 1Z4 Canada

National Center for Advancing Translational Sciences National Institutes of Health Bethesda MD 20892 4874 USA

National Centre for Rare Diseases Istituto Superiore di Sanità Rome 299 00161 Italy

Office of Rare Diseases Research National Center for Advancing Translational Sciences National Institutes of Health Bethesda MD 20892 4874 USA

Orphanet Institut National de la Santé et de la Recherche Médicale US14 75014 Paris France

University of South Florida Health Informatics Institute Tampa FL 33620 USA

Wellcome Trust Sanger Institute Wellcome Trust Genome Campus Hinxton CB10 1SA UK

WuXi AppTec Waigaoqiao Free Trade Zone Shanghai 200131 China; WuXi NextCODE Cambridge MA 02142 USA

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Haploinsufficiency of PRR12 causes a spectrum of neurodevelopmental, eye, and multisystem abnormalities

Enabling Global Clinical Collaborations on Identifiable Patient Data: The Minerva Initiative