The study, "Exome sequencing identifies the cause of a mendelian disorder", was led by University of Washington (UW) researchers and published November 13 in Nature Genetics.
While most mendelian disorders are rare, there are 7000-plus suspected mendelian disorders that in aggregate 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 paediatrics, and a paediatrician 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."
"One of the reasons that this strategy is so powerful is that the scientists need only use a small number of unrelated cases to find the gene", stated the other senior author of the study, Dr. Jay Shendure, UW assistant professor of genome sciences.
Dr. James Kiley, director of the Division of Lung Diseases at the National Heart, Lung and Blood Institute, part of the National Institutes of Healths in Bethesda, Maryland, stated: "Following the recent successes with genome-wide association studies, this promising technology will advance our understanding of the genetic variants of both common disorders and rare diseases."
The disorder the UW research team used to test the strategy is 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 research team was able to find that mutations in the gene, DHODH, cause Miller syndrome.
"Identifying the genetic basis of rare, single-gene diseases is of substantial interest to medical scientists", stated Sarah Ng, a UW genome sciences graduate student and co-first author of the study, "because it provides important knowledge about disease mechanisms, biological pathways, and potential targets for therapies. Once we discover the causative gene, we can begin to look at how the gene might lead to the development of disease and what factors predict the outcome."
After 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 foetuses 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.
The ability of exome sequencing to identify a causative gene in a few months, compared to earlier methods that took years, "caused an audible gasp in the audience when we presented these findings to our peers", Dr. Bamshad stated. "The power of this strategy is remarkable to many of us."
"We hope that the results of this study help point the way for thousands of scientists working on rare disorders who are seeking more efficient ways to locate the causative gene", Dr. Shendure added. "The exome sequencing strategy may also prove useful in studies of common disorders with complex genetics."
The study published in Nature Genetics was a collaborative effort among scientists from many disciplines and institutions. Other authors include co-first author Kati J. Buckingham, from the UW Department of Paediatrics; Choli Lee, UW Department of Genome Sciences; Abigail W. Bigham, UW Department of Paediatrics; Holly K. Tabor, UW Department of Paediatrics and the Treuman Center for Paediatric Bioethics at Seattle Children's; Karin M. Dent and Chad D. Huff from the University of Utah departments of paediatrics and human genetics, respectively; Paul T. Shannon of the Institute of Systems Biology in Seattle; Ethylin Wang Jabs of the Department of Genetics and Genome Sciences at Mount Sinai School of Medicine and the Department of Paediatrics at Johns Hopkins University, and Deborah Nickerson from the UW Department of Genome Sciences.
The research was funded by grants from the Eunice Kennedy Shriver National Institute of Child Health and Health and Human Development, the National Human Genome Research Institute, and the Heart, Lung, and Blood Institute, all at the National Institutes of Health; the state of Washington Life Sciences Discovery Fund and the Washington Research Foundation.