For the first time, researchers have used whole-genome sequencing to track down disease genes in people who have rare inherited disorders. Although the procedure is costly, the scientists say it is a preview of how medical geneticists will routinely diagnosis patients in a few years.
Most of the 10 or so people who have had their genomes completely decoded (such as DNA pioneer James Watson) were not chosen because they had a disease. But James Lupski, a geneticist at Baylor College of Medicine in Houston, Texas, has been eagerly awaiting his turn. Lupski and three of his siblings were born with Charcot-Marie-Tooth disease, which affects nerve function and leads to weak leg and arm muscles. Their form of the disease is recessive, which means they inherited faulty copies of the same gene from both parents. Although the family's DNA has been tested for some genes known to cause Charcot-Marie-Tooth (CMT) disorder, the results were negative.
With sequencing costs falling, Baylor genome sequencer Richard Gibbs's team ran Lupski's DNA through its machines. They then homed in on glitches in 40 genes known to be involved in neurological disorders. They found mutations in both copies of a gene called SH3TC2 that is known to cause CMT disease and is likely involved in nerve transmission. One mutation had never been reported before. Lupski's three sick siblings also had both of these mutations, whereas his four healthy siblings and parents (who do not have the disease) carried only one mutated gene.
"By getting his [Lupski's] complete sequence, we nailed" the mutations, says Gibbs, whose team reports the results today in The New England Journal of Medicine (NEJM). The team also found that family members with just one copy of the mutated gene were prone to carpal tunnel syndrome. That suggests that people who are recessive disease carriers could have more subtle disorders.
The sequencing cost $50,000. As it turns out, the same mutations could have been found by sequencing only the protein-coding regions of the genome—called exome sequencing—for about $4000. But full sequencing will soon be just as cheap as exome sequencing and will catch disease mutations in noncoding regions as well, Gibbs notes.
Meanwhile, another team—reporting in Science Express today—has described the entire genome sequences of a mother and father (both healthy) and their two children, both of whom have two inherited disorders: Miller syndrome and primary ciliary dyskinesia. The study narrowed to four the list of genes that might cause these unrelated diseases. (The specific genes were also reported last fall in Nature Genetics from an exome-sequencing study that included the two children).
Both whole-genome studies show the technique's promise, geneticists say. "These are demonstration projects" that would have been unthinkable 5 years ago, says Yale University geneticist Richard Lifton, who wrote a commentary accompanying the NEJM paper. "In a really short time, we will see new genes discovered on a fairly routine basis."
And that will be a boon to medical geneticists, who now often see patients with all the symptoms of a particular disorder but can’t verify the diagnosis with a genetic test. "It is a godsend to those of us in the field," says Michael Knowles, a medical geneticist at the University of North Carolina, Chapel Hill.