title: Exome sequencing identifies the cause of a mendelian disorder.
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.
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Ng
authors.forename: Kati J
authors.initials: KJ
authors.lastname: Buckingham
authors.forename: Choli
authors.initials: C
authors.lastname: Lee
authors.forename: Abigail W
authors.initials: AW
authors.lastname: Bigham
authors.forename: Holly K
authors.initials: HK
authors.lastname: Tabor
authors.forename: Karin M
authors.initials: KM
authors.lastname: Dent
authors.forename: Chad D
authors.initials: CD
authors.lastname: Huff
authors.forename: Paul T
authors.initials: PT
authors.lastname: Shannon
authors.forename: Ethylin Wang
authors.initials: EW
authors.lastname: Jabs
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bamshad
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000595:Amino Acid Sequence; D000090722:Dihydroorotate Dehydrogenase; D005091:Exons / Q000235:genetics*; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008342:Mandibulofacial Dysostosis / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation; D016366:Open Reading Frames / Q000235:genetics; D044925:Oxidoreductases Acting on CH-CH Group Donors / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods*; D017386:Sequence Homology, Amino Acid; D013577:Syndrome
chemical_list: D000090722:Dihydroorotate Dehydrogenase; D044925:Oxidoreductases Acting on CH-CH Group Donors