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Personal Genome Sequencing Hits Home for Baylor Researcher

Dr. James Lupski (photo) of the Baylor College of Medicine (BCM) came to the end of a long personal quest earlier this year when the Baylor Human Genome Sequencing Center (BHGSC) sequenced his complete genome and identified the gene and mutations involved in his own form of Charcot-Marie-Tooth syndrome, which affects the function of nerves in the body's limbs, hands, and feet. The results were published in the March 11, 2010 issue of the New England Journal of Medicine, a journal chosen, in part, because the authors believe this type of information will be crucial to physicians; as well as to the research community. The authors hope that their results will help begin a new era of clinical sequencing. The sequencing was carried out using next-generation sequencing technology, which has dramatically increased throughput and reduced costs. "This is the first time we have tried to identify a disease gene this way," said Dr. Lupski, Vice Chair of Molecular and Human Genetics at BCM. "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?" According to a summary in Science Now, the BHGSC sequencing effort cost $50,000. As it turns out, the same mutations could have been found by sequencing only the protein-coding regions of the genome—a process called “exome” sequencing—for about $4,000. But full sequencing will soon be just as cheap as exome sequencing and will catch disease mutations in noncoding regions as well, said Dr. Richard Gibbs, Director of the BHGSC.

In the NEJM report, Dr. Lupski, Dr. Gibbs, and collaborators describe the process of the whole genome shotgun study that led to the discovery of two different mutations in the two copies of the SH3TC2 gene that Lupski inherited from his parents. While neither parent has the disease, which affects the peripheral nerves, three of Lupski’s seven siblings also inherited both mutations and have the disease.

"I have the disease and I have two mutant genes," said Dr. Lupski. "I know I have a genetically-recessive disease and I've known that for 40 years."

Now he knows the specific 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," Dr. Lupski 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 like this to see what you might be susceptible to?"

Dr, Lupski and his team identified the first duplication on a chromosome that gave rise to Charcot-Marie-Tooth disease and published that data in 1991. Since that time, mutations or changes in as many as 40 genes have been shown to cause diseases like Charcot-Marie-Tooth.

In this case, Dr. Gibbs and his colleagues sequenced Dr. Lupski's entire genome and identified all the functional variants in genes that were likely to be related to Charcot-Marie-Tooth. In one allele of the SH3TC2 gene pair, the researchers identified a "nonsense" mutation, which means there is a premature stop to the message that results in a protein. This mutation had been reported previously in Charcot-Marie Tooth in particular ethnic groups. They also identified a new “missense” mutation in the second allele. Missense mutations are those in which a single letter in the genetic code [A-T-C-G] is different, in such a way that it results in the production of a different amino acid. This difference can result in a protein that cannot carry out its appointed task in the cell. (Note that “null” mutations are those in which a letter changes, but the same amino acid is produced due to the redundancy of the genetic code).

The nonsense mutation was found in one parent and two siblings who did not have the disease. The missense mutation was found in another parent and one grandparent, neither of whom had the disorder. Only siblings who inherited both mutated genes had the Charcot-Marie-Tooth 1 disorder.

"Clinical and genetics experts struggling with poorly understood high-penetrance genetic diseases must now seriously consider this approach for illuminating the molecular etiology of these cases, and ultimately providing better patient management for families living with such diseases," the authors wrote.

Because they anticipate that this type of information will be valuable to physicians in practice, the authors included a glossary of terms to enhance comprehension of their report.

Again, this research was published in the March 11, 2010 issue of the New England Journal of Medicine. An editorial commenting on the impact of personal whole genome sequencing accompanies the article. [Press release] [NEJM article] [NEJM editorial] [Sciene Now summary]