Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 42 (1), 30-5

Exome Sequencing Identifies the Cause of a Mendelian Disorder


Exome Sequencing Identifies the Cause of a Mendelian Disorder

Sarah B Ng et al. Nat Genet.


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.


Figure 1
Figure 1. Clinical characteristics of an individual with Miller syndrome (A,B) and an individual with methotrexate embryopathy (C,D)
A 9 year-old boy with Miller syndrome (A and B) caused by mutations in DHODH. 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).
Figure 2
Figure 2. Genomic structure of the exons encoding the open reading frame of DHODH
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

Similar articles

See all similar articles

Cited by 815 articles

See all "Cited by" articles


    1. Shendure J, Ji H. Next-generation DNA sequencing. Nature Biotechnology. 2008;26:1135–1145. - PubMed
    1. Ng SB, et al. Targeted capture and massively parallel sequencing of 12 human exomes. Nature. 2009 - PMC - PubMed
    1. Choi M, et al. Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc Natl Acad Sci U S A. 2009 - PMC - PubMed
    1. Hodges E, et al. Genome-wide in situ exon capture for selective resequencing. Nat Genet. 2007;39:1522–7. - PubMed
    1. Stenson PD, et al. The Human Gene Mutation Database: 2008 update. Genome Med. 2009;1:13. - PMC - PubMed

Publication types


LinkOut - more resources