Model Organisms Facilitate Rare Disease Diagnosis and Therapeutic Research

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.

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109. 109.
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110. 110.
     Whole-Exome Sequencing Identifies Homozygous AFG3L2 Mutations in a Spastic Ataxia-Neuropathy Syndrome Linked to Mitochondrial m-AAA Proteases · 2011

     Corrected
111. 111.

     Pollock P. M. Harper U. L. Hansen K. S. Yudt L. M. Stark M., 2003 High frequency of BRAF mutations in nevi. Nat. Genet. 33: 19–20.

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115. 115.
     Non-model model organisms · 2017

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     Drosophila and genome-wide association studies: a review and resource for the functional dissection of human complex traits · 2017

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     Yoon W. H. Sandoval H. Nagarkar-Jaiswal S. Jaiswal M. Yamamoto S., 2017 Loss of Nardilysin, a mitochondrial co-chaperone for alpha-ketoglutarate dehydrogenase, promotes mTORC1 activation and neurodegeneration. Neuron 93: 115–131.

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     Zhang F. Lupski J. R., 2015 Non-coding genetic variants in human disease. Hum. Mol. Genet. 24: R102–R110.

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     Zhang F. Seeman P. Liu P. Weterman M. A. Gonzaga-Jauregui C., 2010 Mechanisms for nonrecurrent genomic rearrangements associated with CMT1A or HNPP: rare CNVs as a cause for missing heritability. Am. J. Hum. Genet. 86: 892–903.

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Cited by papers we hold 3

• A guide for the diagnosis of rare and undiagnosed disease: beyond the exome · 2022
  No notice
• Drosophila Innate Immunity Involves Multiple Signaling Pathways and Coordinated Communication Between Different Tissues · 2022
  No notice
• Genetic Modifiers and Rare Mendelian Disease · 2020
  No notice

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