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Am J Hum Genet. 2015 Aug 6;97(2):199-215. doi: 10.1016/j.ajhg.2015.06.009. Epub 2015 Jul 9.

The Genetic Basis of Mendelian Phenotypes: Discoveries, Challenges, and Opportunities.

Author information

1
Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
2
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA.
3
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
4
Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
5
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
6
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Center for Inherited Disease Research, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
7
McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
8
Johns Hopkins Berman Institute of Bioethics, Baltimore, MD 21205, USA.
9
Division of Medical Genetics, Department of Medicine, University of Washington, Seattle, WA 98195, USA.
10
Department of Genetics and Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, CT 06510, USA.
11
Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Treuman Katz Center for Pediatric Bioethics, Seattle Children's Research Institute, Seattle, WA 98101, USA.
12
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Center for Statistical Genetics, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
13
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
14
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Human Genetics Center, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
15
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
16
Department of Genetics and Yale Center for Genome Analysis, Yale University School of Medicine, New Haven, CT 06510, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
17
Department of Pediatrics, University of Washington, Seattle, WA 98195, USA; Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA; Division of Genetic Medicine, Seattle Children's Hospital, Seattle, WA 98105, USA. Electronic address: mbamshad@uw.edu.

Abstract

Discovering the genetic basis of a Mendelian phenotype establishes a causal link between genotype and phenotype, making possible carrier and population screening and direct diagnosis. Such discoveries also contribute to our knowledge of gene function, gene regulation, development, and biological mechanisms that can be used for developing new therapeutics. As of February 2015, 2,937 genes underlying 4,163 Mendelian phenotypes have been discovered, but the genes underlying ∼50% (i.e., 3,152) of all known Mendelian phenotypes are still unknown, and many more Mendelian conditions have yet to be recognized. This is a formidable gap in biomedical knowledge. Accordingly, in December 2011, the NIH established the Centers for Mendelian Genomics (CMGs) to provide the collaborative framework and infrastructure necessary for undertaking large-scale whole-exome sequencing and discovery of the genetic variants responsible for Mendelian phenotypes. In partnership with 529 investigators from 261 institutions in 36 countries, the CMGs assessed 18,863 samples from 8,838 families representing 579 known and 470 novel Mendelian phenotypes as of January 2015. This collaborative effort has identified 956 genes, including 375 not previously associated with human health, that underlie a Mendelian phenotype. These results provide insight into study design and analytical strategies, identify novel mechanisms of disease, and reveal the extensive clinical variability of Mendelian phenotypes. Discovering the gene underlying every Mendelian phenotype will require tackling challenges such as worldwide ascertainment and phenotypic characterization of families affected by Mendelian conditions, improvement in sequencing and analytical techniques, and pervasive sharing of phenotypic and genomic data among researchers, clinicians, and families.

PMID:
26166479
PMCID:
PMC4573249
DOI:
10.1016/j.ajhg.2015.06.009
[Indexed for MEDLINE]
Free PMC Article

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