Exome Sequencing Identifies the Cause of a Mendelian Disorder

Nat Genet. 2010 Jan;42(1):30-5. doi: 10.1038/ng.499. Epub 2009 Nov 13.

Abstract

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 40x and sufficient depth to call variants at approximately 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / pathology
  • Amino Acid Sequence
  • Exons / genetics*
  • Family Health
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Mandibulofacial Dysostosis / pathology
  • Molecular Sequence Data
  • Mutation
  • Open Reading Frames / genetics
  • Oxidoreductases Acting on CH-CH Group Donors / genetics*
  • Sequence Analysis, DNA / methods*
  • Sequence Homology, Amino Acid
  • Syndrome

Substances

  • Oxidoreductases Acting on CH-CH Group Donors
  • dihydroorotate dehydrogenase