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Selective sequencing solves a genetic mystery

Examining only protein-coding genes finds cause of Miller syndrome.

Sequencing just exons could efficiently identify the genes responsible for some diseases. Credit: Ingram Publishing

Targeted sequencing of the entire protein-coding portion of the human genome has for the first time discovered the cause of a rare genetic disorder.

"This technology is incredibly promising," says James Kiley, director of the division of lung diseases at the National Heart, Lung and Blood Institute in Bethesda, Maryland, which partly funded the work. "It's giving us a more efficient way to identify the causal genetic factors of disease."

Protein-coding genes make up only about 1% of the human genome, but they harbour the bulk of the mutations that contribute the most to disease. So, rather than sequencing entire genomes, many researchers are starting to decode only the protein-coding exons — collectively called the 'exome' — to make genetic inferences at a fraction of the cost of whole-genome sequencing.

In August, a team led by Jay Shendure and Sarah Ng at the University of Washington in Seattle provided the first proof-of-principle that this approach could detect the genetic culprits behind single-gene, or Mendelian, diseases. The researchers sequenced the exomes of 12 unrelated individuals, four of whom had a rare, inherited disorder called Freeman–Sheldon syndrome. Although the genetic defect behind the disease was already known, the technique zeroed in on the exact gene responsible for the disease, demonstrating that it was feasible to sort out the genetic signal from more than 300 million bases of DNA noise1.

"The primary criticism of that paper is that we knew the answer and we were basically showing it could be done," says Shendure. "Here, we're extending that to something where we didn't know the answer."

Tip of the iceberg

Miller syndrome was first described 30 years ago but its cause was a mystery. Credit: Nature Genet., S. B. Ng et al

Shendure and his colleagues have now sequenced the exomes of two siblings and two unrelated individuals who all suffered from a single-gene disorder called Miller syndrome, which is characterized by facial malformations and limb abnormalities, such as a cleft palate and absent or webbed fingers and toes. Although the disease was first described 30 years ago, its genetic basis has remained elusive.

The researchers compared the exomes of Miller-affected individuals to exome sequences from eight healthy, unrelated individuals. This approach flagged a single candidate gene called DHODH, which encodes an enzyme that is essential for making some of the building blocks used in DNA and RNA. Shendure's team then directly sequenced DHODH in four more Miller-affected individuals and found that they too all had mutations in this gene. No similar mutations were found in 100 unaffected individuals. The findings are published online today in Nature Genetics2.

"This is the first demonstration of whole-exome sequencing for a new disease-gene discovery," says Richard Lifton, a geneticist at Yale University School of Medicine in New Haven, Connecticut, who was not involved in the work. This first discovery is only the tip of the iceberg, he adds. "I think there are large classes of Mendelian traits that will be found by whole-exome sequencing."

Lifton also notes that exome sequencing will be useful as a clinical tool. In October, Lifton and his colleagues used the technique to diagnose a five-month-old child with a mysterious genetic illness. They found that the infant, who was suffering from persistent dehydration and a lack of weight gain, had a mutation in a gene that caused intestinal problems due to congenital chloride diarrhoea, not in a kidney-associated gene as physicians had originally suspected3.

Shendure is confident that exome sequencing can reliably uncover genes that are responsible for relatively simple, single-gene disorders. The big challenge moving forward, he says, is to show that the method can tease apart the genetic basis of more-complex diseases in which two or more genes are involved. "That's by no means a given," he says. "This is going to be hard."


  1. Ng, S. B. et al. Nature 461, 272-276 (2009).

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  2. Ng, S. B. et al. Nature Genet. advance online publication doi:10.1038/ng.499 (2009).

  3. Choi, M. et al. Proc. Natl Acad. Sci. USA 106, 19096-19101 (2009).

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NHLBI's Exome Project

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Dolgin, E. Selective sequencing solves a genetic mystery. Nature (2009).

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