Exome Sequencing Identifies Rare Mendelian Disorder

Their results indicate that exome-sequencing might help identify the genetic cause of thousands of disorders.

Mendelian disorders, such as cystic fibrosis and sickle cell disease, are the result of one or more mutations in a single gene, typically a gene that makes a protein. All of the regions that code for proteins taken together are called the exome. The exome makes up about 1% of the genome, but in this 1% more than 85% of mutations that cause Mendelian disorders are found. That is why sequencing the exome is an efficient strategy to search for genes that are responsible rare genetic disorders.

A University of Washington (UW; Seattle, USA) team used exome sequencing to investigate the cause of Miller syndrome, whose genetic cause had been impossible to determine through conventional approaches. People with this syndrome have a number of malformations affecting their mouths, eyelids, ears, and feet. The team discovered that mutations in the gene, DHODH, were the cause of Miller syndrome. The study was described in the November 13, 2009 issue of Nature Genetics.

There are 7,000-plus suspected Mendelian disorders that affect millions of people in the United States, according to Dr. Michael J. Bamshad, one of the senior authors of the study, a UW professor of genome sciences and pediatrics, and a pediatrician at Seattle Children's. "Our results show that scientists could use exome sequencing to identify the genetic cause for thousands of disorders for which the gene hasn't been discovered."

When scientists identify one causative gene and its repercussions, by extension they might discover other genes or environmental agents that affect the same biological pathway. For example, the malformation patterns found in Miller syndrome are similar to the birth defects in fetuses of some, but not all, mothers who took the drug methotrexate during pregnancy. Knowing this might provide some clues to genetic susceptibility to birth defects from methotrexate.

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