Abstract
Efforts to identify the genetic underpinnings of rare undiagnosed diseases increasingly involve the use of next-generation sequencing and comparative genomic hybridization methods. These efforts are limited by a lack of knowledge regarding gene function, and an inability to predict the impact of genetic variation on the encoded protein function. Diagnostic challenges posed by undiagnosed diseases have solutions in model organism research, which provides a wealth of detailed biological information. Model organism geneticists are by necessity experts in particular genes, gene families, specific organs, and biological functions. Here, we review the current state of research into undiagnosed diseases, highlighting large efforts in North America and internationally, including the Undiagnosed Diseases Network (UDN) (Supplemental Material, File S1) and UDN International (UDNI), the Centers for Mendelian Genomics (CMG), and the Canadian Rare Diseases Models and Mechanisms Network (RDMM). We discuss how merging human genetics with model organism research guides experimental studies to solve these medical mysteries, gain new insights into disease pathogenesis, and uncover new therapeutic strategies.
Highlights
Efforts to identify the genetic underpinnings of rare undiagnosed diseases increasingly involve the use of next-generation sequencing and comparative genomic hybridization methods
The questions we raised about the future of model organism research, and subsequent discussion at The Allied Genetics Conference in 2016, which included the Director of the National Institutes of Health (NIH), made clear the priority that model organism research should have in biomedical research
We primarily focus on two model organisms—Drosophila and zebrafish (Figure 1)—and highlight large-scale efforts in the United States (US) and Canada that integrate model organisms into human disease diagnosis and therapy development
Summary
Wangler,*,†,‡,§,1 Shinya Yamamoto,*,‡,§,**,1 Hsiao-Tuan Chao,†,‡,†† Jennifer E. Monte Westerfield,‡‡ John Postlethwait,‡‡ Members of the Undiagnosed Diseases Network (UDN),. Bellen*,‡,§,**,‡‡‡,3 *Department of Molecular and Human Genetics, †Department of Pediatrics, §Program in Developmental Biology, **Department of Neuroscience, ††Department of Pediatrics, Section of Child Neurology, and ‡‡‡Howard Hughes Medical Institute, Baylor College of Medicine (BCM), Houston, Texas 77030, ‡Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, Texas 77030, ‡‡Institute of Neuroscience, University of Oregon, Eugene, Oregon 97403, §§Michael Smith Laboratories, University of British Columbia, Vancouver, British Columbia V6T 1Z4C, Canada, ***Children’s Hospital of Eastern Ontario Research Institute, University of Ottawa, Ontario K1H 8L1, Canada, †††Department of Pediatrics, University of Montreal, Quebec H3T 1C5, Canada. ORCID IDs: 0000-0001-5245-5910 (M.F.W.); 0000-0003-2172-8036 (S.Y.); 0000-0003-4814-6765 (J.E.P.); 0000-0002-5476-2137 (J.P.); 0000-0003-4186-8052 (K.M.B.); 0000-0001-9713-7107 (P.M.C.); 0000-0001-5992-5989 (H.J.B.)
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