Charcot-Marie Tooth Gene Identified After Complete Genome Sequencing

James Lupski, MD, PhD, vice chair of molecular and human genetics at Baylor College of Medicine (BCM) came to the end of a personal quest earlier this year when the Baylor Human Genome Sequencing Center sequenced his complete genome and identified the gene involved in his own form of Charcot-Marie-Tooth syndrome, which affects the function of nerves in the body’s limbs, hands and feet. At the same time, the finding opened a new door showing that genome information has clinical importance.

“This is the first time we have tried to identify a disease gene this way,” Lupski said in a news release. “It demonstrates that the technology is robust enough that we can find disease genes by determining the whole genome sequence. We can start to use this technology to interpret the clinical information in the context of the sequence – of the hand of cards you have been dealt. Isn’t that the goal or dream of personalized genomic medicine?”

In a report, Lupski, Richard Gibbs, MD, director of the Human Genome Sequencing Center and other experts described the process of the whole genome shotgun study that led to the discovery of different mutations in the copies of the gene SH3TC2 that Lupski inherited from his parents. While neither parent has the disease, which affects the peripheral nerves, four of their children inherited both mutations and had the disease.

“I have the disease and I have two mutant genes,” Lupski said. “I know I have a genetically-recessive disease and I’ve known that for 40 years.”

Now he knows the gene at fault. In taking the research further, he and his colleagues also found that a person who carries only one of the recessive mutations is susceptible to carpal tunnel syndrome. This disorder usually affects people who perform repetitive motions that compress the median nerve where it crosses the wrist.

“I wonder how often this occurs,” he said. “People who carry one gene for a recessive disease may have susceptibility for complex traits. Will we be able to look at some alleles (gene copies) like this to see what you might be susceptible to?”

To date, fewer than 10 personal genomes have been completed – most of them an intellectual exercise. Because Lupski and Gibbs anticipate that this information will be valuable to physicians in practice, they included a glossary of terms relating to DNA sequencing to enhance comprehension of their report. Lupski and Gibbs both hope that this begins a new era of clinical sequencing.

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