doi: 10.1038/ng.499. Epub 2009 Nov 13.
Exome sequencing identifies the cause of a mendelian disorder
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- PMID:19915526
- PMCID: PMC2847889
- DOI: 10.1038/ng.499
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Exome sequencing identifies the cause of a mendelian disorder
Sarah B Ng et al. Nat Genet.2010 Jan.
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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.
Figures
A 9 year-old boy with Miller syndrome (A and B) caused by mutations inDHODH. Facial anomalies (A) include cupped ears, coloboma of the lower eyelids, prominent nose, micrognathia and absence of the 5th digits of the feet (B). A 26 year-old man with methotrexate embryopathy (C and D). Note the cupped ears, hypertelorism, sparse eyebrows, and prominent nose (C) accompanied by absence of the 4th and 5th digits of the feet (D). C and D are reprinted with permission from Bawle et al.Teratology 57:51-55 (1978).
DHODH is composed of 9 exons that encode untranslated regions (orange) and protein coding sequence (blue). Arrows indicate the locations of 11 different mutations found in 6 families with Miller syndrome.
Comment in
- Exome sequencing makes medical genomics a reality.Biesecker LG.Biesecker LG.Nat Genet. 2010 Jan;42(1):13-4. doi: 10.1038/ng0110-13.Nat Genet. 2010.PMID:20037612
- Exome sequencing: locating causative genes in rare disorders.Pussegoda KA.Pussegoda KA.Clin Genet. 2010 Jul;78(1):32-3. doi: 10.1111/j.1399-0004.2010.01414_1.x.Clin Genet. 2010.PMID:20597920No abstract available.
- Exome sequencing: expanding the genetic testing toolbox.Kobelka CE.Kobelka CE.Clin Genet. 2010 Aug;78(2):132-4. doi: 10.1111/j.1399-0004.2010.01452_1.x.Clin Genet. 2010.PMID:20662854No abstract available.
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