Exome sequencing identifies the cause of a mendelian disorder

Journal name:
Nature Genetics
Year published:
Published online


We demonstrate the first successful application of exome sequencing to discover the gene for a rare mendelian disorder of unknown cause, Miller syndrome (MIM%263750). For four affected individuals in three independent kindreds, we captured and sequenced coding regions to a mean coverage of 40× and sufficient depth to call variants at ~97% of each targeted exome. Filtering against public SNP databases and eight HapMap exomes for genes with two previously unknown variants in each of the four individuals identified a single candidate gene, DHODH, which encodes a key enzyme in the pyrimidine de novo biosynthesis pathway. Sanger sequencing confirmed the presence of DHODH mutations in three additional families with Miller syndrome. Exome sequencing of a small number of unrelated affected individuals is a powerful, efficient strategy for identifying the genes underlying rare mendelian disorders and will likely transform the genetic analysis of monogenic traits.

At a glance


  1. Clinical characteristics of an individual with Miller syndrome and an individual with methotrexate embryopathy.
    Figure 1: Clinical characteristics of an individual with Miller syndrome and an individual with methotrexate embryopathy.

    (a,b) A 9-year-old boy with Miller syndrome caused by mutations in DHODH. Facial anomalies (a) include cupped ears, coloboma of the lower eyelids, prominent nose, micrognathia and absence of the fifth digits of the feet (b). (c,d) A 26-year-old man with methotrexate embryopathy. Note the cupped ears, hypertelorism, sparse eyebrows and prominent nose (c) accompanied by absence of the fourth and fifth digits of the feet (d). c and d are reprinted with permission from ref. 30.

  2. Genomic structure of the exons encoding the open reading frame of DHODH.
    Figure 2: Genomic structure of the exons encoding the open reading frame of DHODH.

    DHODH is composed of nine exons that encode untranslated regions (UTR) (orange) and protein coding sequence (blue). Arrows indicate the locations of 11 different mutations found in 6 families with Miller syndrome.

Change history

22 November 2009
In the version of this article initially published online, the panels of Figure 1 were incorrectly labeled. The error has been corrected for the print, PDF and HTML versions of this article.


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Author information

  1. These authors contributed equally to this work.

    • Sarah B Ng &
    • Kati J Buckingham


  1. Department of Genome Sciences, University of Washington, Seattle, Washington, USA.

    • Sarah B Ng,
    • Choli Lee,
    • Deborah A Nickerson,
    • Jay Shendure &
    • Michael J Bamshad
  2. Department of Pediatrics, University of Washington, Seattle, Washington, USA.

    • Kati J Buckingham,
    • Abigail W Bigham,
    • Holly K Tabor &
    • Michael J Bamshad
  3. Treuman Katz Center for Pediatric Bioethics, Seattle Children's Hospital, Seattle, Washington, USA.

    • Holly K Tabor
  4. Department of Pediatrics, University of Utah, Salt Lake City, Utah, USA.

    • Karin M Dent
  5. Department of Human Genetics, University of Utah, Salt Lake City, Utah, USA.

    • Chad D Huff
  6. Institute of Systems Biology, Seattle, Washington, USA.

    • Paul T Shannon
  7. Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, New York, USA.

    • Ethylin Wang Jabs
  8. Department of Pediatrics, Johns Hopkins University, Baltimore, Maryland, USA.

    • Ethylin Wang Jabs
  9. Seattle Children's Hospital, Seattle, Washington, USA.

    • Michael J Bamshad


The project was conceived and experiments planned by M.J.B., D.A.N. and J.S. Review of phenotypes and sample collection were performed by E.W.J. and M.J.B. Experiments were performed by S.B.N., K.J.B. and C.L. Genetic counseling and ethical consultation were provided by K.M.D. and H.K.T. Data analysis were performed by S.B.N., K.J.B., A.W.B., C.D.H., P.T.S. and J.S. The manuscript was written by M.J.B., J.S., S.B.N. and K.J.B. All aspects of the study were supervised by M.J.B., D.A.N. and J.S.

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