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

Jessica X. Chong, Kati J. Buckingham, Shalini N. Jhangiani, Corinne Boehm, Nara Sobreira, Joshua D. Smith, Tanya M. Harrell, Margaret J. McMillin, Wojciech Wiszniewski, Tomasz Gambin, Zeynep H. Coban Akdemir, Kimberly Doheny, Alan F. Scott, Dimitri Avramopoulos, Aravinda Chakravarti, Julie Hoover-Fong, Debra Mathews, P. Dane Witmer, Hua Ling, Kurt HetrickLee Watkins, Karynne E. Patterson, Frederic Reinier, Elizabeth Blue, Donna Muzny, Martin Kircher, Kaya Bilguvar, Francesc López-Giráldez, V. Reid Sutton, Holly K. Tabor, Suzanne M. Leal, Murat Gunel, Shrikant Mane, Richard A. Gibbs, Eric Boerwinkle, Ada Hamosh, Jay Shendure, James R. Lupski, Richard P. Lifton, David Valle, Deborah A. Nickerson, Michael J. Bamshad

Research output: Contribution to journalReview articlepeer-review

469 Scopus citations


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.

Original languageEnglish (US)
Article number1908
Pages (from-to)199-215
Number of pages17
JournalAmerican Journal of Human Genetics
Issue number2
StatePublished - Aug 6 2015
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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