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Exome Sequencing IDs Mendelian Disease Culprit

HONOLULU (GenomeWeb News) – Researchers from the University of Washington used exome sequencing to identify mutations causing a rare, single gene condition called Miller syndrome, attendees at the American Society of Human Genetics heard here this week.

In a plenary session on Wednesday afternoon, University of Washington genomics researcher Jay Shendure described how his team's applied whole exome sequencing to identify the mutations in the dihydroorotate oxidase gene (DHODH) in four individuals with Miller syndrome. He had presented initial findings on the research, which was covered by GenomeWeb Daily News sister publication In Sequence, last month at the Personal Genomes conference at Cold Spring Harbor Laboratory.

An estimated 80 percent of the causative mutations behind rare mongenic diseases occur in protein-coding regions of the genome, Shendure's colleague, University of Washington genetics and developmental medicine researcher Michael Bamshad, told reporters during a press briefing this week.

As such, he explained, exome sequencing holds promise for finding these mutations more quickly and affordably than whole-genome sequencing and analysis.

Shendure, Bamshad, and their co-workers recently published a paper in Nature in which they sequenced the exomes of a dozen individuals: eight from the HapMap Project and four with a monogenic, autosomal dominant disease called Freeman-Sheldon syndrome. In that proof-of-principle work, the team demonstrated that they could find mutations in the gene MYH3 that were already known to cause Freeman-Sheldon syndrome.

For the latest study, the team turned their attention to a rare autosomal recessive condition called Miller syndrome. The condition, characterized by facial and limb abnormalities, was first identified 30 years ago. But researchers have been searching for the affected gene for about a decade, Bamshad said, and the cause of Miller syndrome remained elusive.

Using Agilent microarrays and the Illumina Genome Analyzer IIx, the team sequenced the exomes of four children with Miller syndrome from three families.

In so doing, they identified Miller syndrome-related mutations in DHODH, a highly conserved gene coding for a key enzyme in the pyrimidine biosynthesis pathway — results that they confirmed by sequencing the gene in another six individuals with Miller syndrome.

That suggests the condition is actually an inborn error of metabolism, Shendure explained. Indeed, he added, the features of Miller syndrome are quite similar to birth defects caused by prenatal exposure to the cancer and autoimmune drug methotrexate, which inhibits purine and pyrimidine biosynthesis.

Two siblings in the study also had a cystic fibrosis-like lung condition. In these children the team found mutations in a second gene called DNAH5, Shendure noted, indicating that they might actually have two different Mendelian diseases simultaneously.

"This is obviously now a potential tool to identify the genetic basis for thousand of monogenic disorders for which we have not yet found the gene," Bamshad said. "We think it's a strategy that's going to literally revolutionize the way we look at monogenic disorders."

Last week, a Yale University-led team reported in the Proceedings of the National Academy of Sciences that they had used whole exome sequencing with Roche Nimblegen exome capture arrays and Illumina sequencing to diagnose congenital chloride diarrhea in a Turkish infant.

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