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NIH Research Matters

NIH Research Matters

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March 22, 2010

Whole-Genome Analyses Pinpoint Disease Genes in Families

Two independent research teams have, for the first time, used whole-genome sequencing to diagnose disease at the molecular level in families with a genetic disorder. The results offer a preview of the potential benefits of using genome sequencing and personalized medicine as a routine part of medical care.

Illustration of DNA.

Despite technological advances that have made genome sequencing faster and more affordable in recent years, only a dozen people worldwide have reportedly had their entire genomes sequenced. Researchers often find it more practical to sequence smaller, targeted regions that are most likely to carry abnormal or unusual genes. Although these shortcuts are effective, the new whole-genome studies show the benefits of a broader approach.

In one study, supported in part by NIH's National Institute of General Medical Sciences (NIGMS), Dr. David Galas of the Institute for Systems Biology in Seattle worked with colleagues to analyze the whole genomes of all 4 members of a family. Two siblings each had 2 rare disorders—Miller syndrome, marked by facial and limb defects, and primary ciliary dyskinesia, which affects the lungs—but their 2 parents did not. The research is described in the March 11, 2010, early online edition of Science.

Whole-genome sequencing allowed the researchers to identify the precise locations where the parents' DNA recombined to pass along a new mix of traits to their children. They identified 4 candidate genes that likely cause the rare disorders in this family. In addition, the genome comparisons allowed the scientists to accurately estimate the rate at which mutations arise between parents and children.

"We were very pleased and a little surprised at how much additional information can come from examining the full genomes of the same family," says Galas. "We can now see all the genetic variations, including rare ones, and can construct the inheritance of every piece of the chromosomes, which is critical to understanding the traits important to health and disease."

In the second study, Dr. James Lupski of Baylor College of Medicine was the subject of his own research. He had been diagnosed with Charcot-Marie-Tooth (CMT) disease, a rare inherited disorder that affects nerve function in the limbs, hands and feet. Three of his 7 siblings also had CMT, but his parents did not. Previous screenings showed that the family did not have some of the most common gene variants linked to CMT.

With support from NIH’s National Institute of the Neurological Disorders and Stroke (NINDS) and National Human Genome Research Institute (NHGRI), the researchers sequenced Lupski's entire genome and identified tiny gene variants that might be related to CMT. They then analyzed these variants in Lupski's parents and siblings.

In the March 10, 2010, online edition of the New England Journal of Medicine, the scientists report that Lupski and other affected family members carried 2 altered versions of the gene SH3TC2, which was previously linked to CMT. Most unaffected family members, including both parents, had just a single copy of the gene variant.

"This study is an impressive use of next-generation genome sequencing technology to probe the underlying causes of CMT," says NINDS Director Dr. Story Landis.

These new sequencing methods could potentially aid in the diagnosis of a variety of disorders. Knowing which mutations affect each patient would help doctors personalize treatments to target faulty molecular pathways and perhaps avoid unwanted side effects.

—by Vicki Contie

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About NIH Research Matters

Editor: Harrison Wein, Ph.D.
Assistant Editors: Vicki Contie, Carol Torgan, Ph.D.

NIH Research Matters is a weekly update of NIH research highlights from the Office of Communications and Public Liaison, Office of the Director, National Institutes of Health.

This page last reviewed on December 3, 2012

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