Nov 17, 2009

Exome sequencing identifies the cause of a mendelian disorder

Nature Genetics
Sarah B NgMichael J Bamshad

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.

  • References30
  • Citations1043

References

Mentioned in this Paper

Chromosome 11p Deletion Syndrome
Genee-Wiedemann Syndrome
Biochemical Pathway
Family Health Status
Oxidoreductases Acting on CH-CH Group Donors
Genetic Analysis
Genetic Screening Method
Dihydroorotate dehydrogenase
Candidate Disease Gene
Homologous Sequences, Amino Acid

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