Identifying genes and variants contributing to rare disease phenotypes and Mendelian conditions informs biology and medicine, yet potential phenotypic consequences for variation of >75% of the ~20,000 annotated genes in the human genome are lacking. Technical advances to assess rare variation genome-wide, particularly exome sequencing (ES), enabled establishment in the United States of the National Institutes of Health (NIH)-supported Centers for Mendelian Genomics (CMGs) and have facilitated collaborative studies resulting in novel “disease gene” discoveries. Pedigree-based genomic studies and rare variant analyses in families with suspected Mendelian conditions have led to the elucidation of hundreds of novel disease genes and highlighted the impact of de novo mutational events, somatic variation underlying nononcologic traits, incompletely penetrant alleles, phenotypes with high locus heterogeneity, and multilocus pathogenic variation. Herein, we highlight CMG collaborative discoveries that have contributed to understanding both rare and common diseases and discuss opportunities for future discovery in single-locus Mendelian disorder genomics. Phenotypic annotation of all human genes; development of bioinformatic tools and analytic methods; exploration of non-Mendelian modes of inheritance including reduced penetrance, multilocus variation, and oligogenic inheritance; construction of allelic series at a locus; enhanced data sharing worldwide; and integration with clinical genomics are explored. Realizing the full contribution of rare disease research to functional annotation of the human genome, and further illuminating human biology and health, will lay the foundation for the Precision Medicine Initiative.

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The Baylor Hopkins Center for Mendelian Genomics, Broad Institute Harvard Center for Mendelian Genomics, University of Washington Center for Mendelian Genomics, and Yale Center for Mendelian Genomics were funded by the National Human Genome Research Institute (NHGRI) awards UM1 HG006542, UM1 HG008900, UM1 HG006493, and UM1 HG006504, respectively. Funds were also provided under the National Heart, Lung, and Blood Institute (NHLBI) under the Trans-Omics for Precision Medicine Program (TOPMed), and the National Eye Institute (NEI). The GSP Coordinating Center (U24 HG008956) contributed to cross-program scientific initiatives and provided logistical and general study coordination. Funds were also provided under the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD R03 HD092569) to C.M.B.C. and V.R.S. J.E.P. was supported by NHGRI K08 HG008986. A.H.O.-L. was supported by National Institute of Child Health and Human Development (NICHD) K12 HD052896. N.W. was supported by National Natural Science Foundation of China (81501852), Beijing Natural Science Foundation (7172175), and 2016 Milstein Medical Asian American Partnership Foundation Fellowship Award in Translational Medicine. This work was also supported by the National Institute of Neurological Disorders and Stroke (NINDS) R35 NS105078 to J.R.L.

Author information


  1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA

    • Jennifer E. Posey MD, PhD
    • , Zeynep H. Coban Akdemir PhD
    • , Davut Pehlivan MD
    • , Claudia M. B. Carvalho PhD
    • , Pengfei Liu PhD
    • , Nan Wu MD
    • , Jill A. Rosenfeld MS, CGC
    • , Janson J. White PhD
    • , V. Reid Sutton MD
    • , Richard A. Gibbs PhD
    •  & James R. Lupski MD, PhD, DSc (hon)
  2. Analytic and Translational Genetics Unit, Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA

    • Anne H. O’Donnell-Luria MD, PhD
    • , Daniel G. MacArthur PhD
    •  & Heidi L. Rehm PhD
  3. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    • Anne H. O’Donnell-Luria MD, PhD
    • , Samantha Baxter MS, CGC
    • , Daniel G. MacArthur PhD
    •  & Heidi L. Rehm PhD
  4. Boston Children′s Hospital, Boston, MA, USA

    • Anne H. O’Donnell-Luria MD, PhD
  5. Department of Pediatrics, University of Washington, Seattle, WA, USA

    • Jessica X. Chong PhD
    • , Janson J. White PhD
    •  & Michael J. Bamshad MD
  6. Department of Genetic and Metabolic Diseases, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

    • Tamar Harel MD, PhD
  7. The Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA

    • Shalini N. Jhangiani MS
    • , Donna M. Muzny MS
    • , Eric Boerwinkle PhD
    • , Richard A. Gibbs PhD
    •  & James R. Lupski MD, PhD, DSc (hon)
  8. Department of Genetics, Rutgers University, Piscataway, NJ, USA

    • Steven Buyske PhD
    •  & Tara C. Matise PhD
  9. Department of Statistics, Rutgers University, Piscataway, NJ, USA

    • Steven Buyske PhD
  10. McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, MD, USA

    • Nara Sobreira MD, PhD
    • , Dimitri Avramopoulos MD, PhD
    • , Kimberly F. Doheny PhD
    • , P. Dane Witmer PhD
    • , Corinne Boehm MS, CGC
    • , Ada Hamosh MD
    •  & David Valle MD
  11. Baylor Genetics Laboratory, Houston, TX, USA

    • Pengfei Liu PhD
  12. Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China

    • Nan Wu MD
  13. Computational Biology and Bioinformatics Program, Yale University Medical School, New Haven, CT, USA

    • Sushant Kumar PhD
    •  & Mark Gerstein PhD
  14. Center for Inherited Disease Research, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    • Kimberly F. Doheny PhD
    •  & P. Dane Witmer PhD
  15. Human Genetics Center, University of Texas Health Science Center, Houston, TX, USA

    • Eric Boerwinkle PhD
  16. Department of Neurosurgery, Yale School of Medicine, New Haven, CT, USA

    • Murat Günel MD
    •  & Richard P. Lifton MD, PhD
  17. Department of Genetics, Yale School of Medicine, New Haven, CT, USA

    • Murat Günel MD
  18. Department of Genome Sciences, University of Washington, Seattle, WA, USA

    • Deborah A. Nickerson PhD
    •  & Michael J. Bamshad MD
  19. Yale Center for Genome Analysis, Yale School of Medicine, Yale University, New Haven, CT, USA

    • Shrikant Mane PhD
  20. Department of Internal Medicine, Yale University School of Medicine, New Haven, CT, USA

    • Richard P. Lifton MD, PhD
  21. Laboratory of Human Genetics and Genomics, The Rockefeller University, New York, NY, USA

    • Richard P. Lifton MD, PhD
  22. Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA

    • James R. Lupski MD, PhD, DSc (hon)
  23. Texas Children’s Hospital, Baylor College of Medicine, Houston, TX, USA

    • James R. Lupski MD, PhD, DSc (hon)


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  1. Centers for Mendelian Genomics


    Baylor College of Medicine (BCM) and Miraca Holdings Inc. have formed a joint venture with shared ownership and governance of Baylor Genetics (BG), formerly the Baylor Miraca Genetics Laboratories (BMGL), which performs clinical exome sequencing and chromosomal microarray analysis for genome-wide detection of CNV. J.R.L. serves on the Scientific Advisory Board of BG. J.R.L. has stock ownership in 23andMe, is a paid consultant for Regeneron Pharmaceuticals, and is a coinventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases and bacterial genomic fingerprinting. The other authors declare no conflicts of interest.

    Corresponding authors

    Correspondence to Jennifer E. Posey MD, PhD or James R. Lupski MD, PhD, DSc (hon).

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