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U of Wash-Led Team Publishes Miller Syndrome Exome Sequencing Paper

NEW YORK (GenomeWeb News) – American researchers who used exome sequencing to find mutations behind a rare single gene disease called Miller syndrome have published the results of the study. The research appeared in the advance, online edition of Nature Genetics yesterday afternoon.

By sequencing the protein-coding regions of the genome for four individuals with Miller syndrome from three families, the University of Washington-led team found mutations in a gene called DHODH, which codes for an enzyme in the pyrimidine biosynthesis pathway.

The study is a follow-up to the group's proof-of-principle publication in Nature this summer showing that they could identify the previously identified gene involved in a monogenic disease called Freeman-Sheldon syndrome by sequencing the exomes of four affected individuals and eight HapMap individuals.

More recently, the team turned their attention to another rare Mendelian disease called Miller syndrome, which is characterized by an under-sized jaw, droopy eyes, cleft lip or palate, incomplete or unusual limb development.

Study co-author Jay Shendure, a researcher with the University of Washington's Department of Genome Sciences, reported results from the Miller syndrome study at the American Society of Human Genetics meeting in Honolulu last month and September's Personal Genomes meeting at the Cold Spring Harbor Laboratory.

To find the affected gene, the researchers focused on four individuals with Miller syndrome: two siblings from the same family and two other unrelated individuals. After enriching for exome sequence with Agilent microarrays, the team sequenced each exome to a mean coverage of about 40 times using an Illumina Genome Analyzer II.

By looking for mutations that didn't appear in the public SNP database dbSNP129 and the eight previously sequenced HapMap exomes, the team honed in on 26 candidate genes that fit a dominant model for Miller syndrome and just one gene — DHODH — that was consistent with a recessive model of the disease.

The researchers verified a role for DHODH in Miller syndrome by using Sanger sequencing to find mutations in the gene in three more affected families.

Together, the team's exome sequencing and targeted re-sequencing efforts turned up 11 DHODH mutations in six affected families — changes that were not detected when the team genotyped 200 unaffected controls.

And consistent with a recessive inheritance model for Miller syndrome, all of the parents of children with Miller syndrome were heterozygous carriers for DHODH mutations.

In addition, the researchers discovered that the siblings carried another mutated gene — DNAH5 — that appears to be involved in a lung condition that those two individuals have called primary ciliary dyskinesia.

"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," the team wrote.

Despite the team's success in using exome sequencing to find monogenic disease culprits, they say there is still room for improvement. For instance, they noted that the current approach might miss some variants, particularly those found in repeat regions. And, they added, currently available public databases don't evenly represent variants across the entire genome.

"[A]s increasingly deep catalogs of polymorphism become available, it may be necessary to establish frequency-based thresholds for defining common variation that is unlikely to be causal for disease," they wrote.

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