James Lupski, a physician-scientist who suffers from a neurological disorder called Charcot-Marie-Tooth, has been searching for the genetic cause of his disease for more than 25 years. Late last year, he finally found it--by sequencing his entire genome. While a number of human genome sequences have been published to date, Lupski's research is the first to show how whole-genome sequencing can be used to identify the genetic cause of an individual's disease.

The project, published today in the New England Journal of Medicine, reflects a new approach to the hunt for disease-causing genes--an approach made possible by the plunging cost of DNA sequencing. Part of a growing trend in the field, the study incorporates both new technology and a more traditional method of gene-hunting that involves analyzing families with rare genetic diseases. A second study, the first to describe the genomes of an entire family of four, confirmed the genetic root of a rare disease, called Miller syndrome, afflicting both children. That study was published online yesterday in Science.

While the approach is currently limited to rare genetic diseases, researchers hope it will ultimately enable the discovery of rare genetic variants increasingly thought to lie at the root of even common diseases, such as diabetes and heart disease.

Lupski was diagnosed as a teenager with Charcot-Marie-Tooth, a disorder that strikes about one in 2,500 people and affects sensory and motor nerves and leads to weaknesses of the foot and leg muscles. Three of his seven siblings also have the disease. While the disorder has a number of different forms and can be caused by a number of genetic mutations, it appears to be recessive in Lupski's family, meaning that an individual must carry two copies of the defective gene to have it.

Decades later, in 1991, after Lupski had trained as both a molecular biologist and a medical geneticist, his lab at Baylor College of Medicine, in Houston, identified the first genetic mutation linked to Charcot-Marie-Tooth. It was a duplication of a gene on chromosome 17 that is involved in producing the fatty insulation that covers nerve fibers, as well as several other genes tied to the disease. "Every time we discovered a new gene, we put my DNA in the group of samples to be sequenced," says Lupski. But those studies failed to identify the mutation responsible for his case. To date, 29 genes and nine genetic regions have been linked to the disease.

In 2007, Lupski and colleague Richard Gibbs, director of the Human Genome Sequencing Center at Baylor, helped sequence James Watson's genome, the first personal genome sequence to be published (aside from that of Craig Venter, who used his own DNA in the private arm of the Human Genome Project). The problem with that project was that, thanks to Watson's good health, there was little clinical relevance to his genome--he had no diseases to try to match to a gene. So Gibbs offered to turn the genome center's sequencing power on Lupski.

Using technology from Applied Biosystems, a sequencing company based in Foster City, CA, the researchers generated about 90 gigabytes of raw sequence data, covering Lupski's genome approximately 30 times. (Because of unavoidable errors in sequencing, a human genome must be analyzed a number of times to generate an accurate read.) They then identified spots where his genome differed from that of the reference sequence from the Human Genome Project, and narrowed that pool down to novel variations found in genes previously linked to Charcot-Marie-Tooth or other nerve disorders. Researchers found that Lupski's genome carried two different mutations in a gene called SH3TG2, which had been previously tied to the disorder. The team then sequenced the gene in DNA from his siblings, parents, and deceased grandparents. (In preparation for this discovery, the scientist had collected his family's DNA 25 years ago.) All of his affected siblings also carried both of the mutations, while the unaffected family members carried either one or neither, exactly the pattern for a recessive disease.