BioEd Online

By sequencing the genomes of three patients with rare genetic disorders, and comparing them with genetic information from unaffected family members, two studies have managed to narrow down the causes of the diseases.

Between them, the analyses bring the number of individuals who have had their full genomes sequenced from seven to twelve.

A team led by David Galas of the Institute for Systems Biology in Seattle, Washington, sequenced the genomes of a family of four in which the two children had extremely rare genetic disorders — Miller syndrome and primary ciliary dyskinesia¹. Miller syndrome causes facial and limb abnormalities, and primary ciliary dyskinesia prevents hair-like structures in the respiratory tract from removing mucus.

By comparing the genomes of the children with those of the unaffected parents, the team was able to pinpoint the specific recombinations of parental genes that led to the diseases, and eliminate other parts of the genome that previous studies had associated with the disorders. The researchers conclude that just four genes underlie the two diseases.

Scientist studied

And in a second analysis, author James Lupski became a subject of his own study. A molecular geneticist at Baylor College of Medicine in Houston, Texas, Lupski has a rare variation of Charcot-Marie-Tooth disease, which causes a loss of muscle and nerve function in the limbs, hands and feet. Having come up with no firm results in previous screenings of Lupski's family, scientists had puzzled over the genetic cause of the disease. But by sequencing Lupski's entire genome and comparing it with snippets from his family members, Lupski's colleagues have identified new mutations associated with his disease².

First, Lupski and his colleagues compared his genome to the human genome reference sequence to identify places where single bases of DNA had been substituted. Of the genes they identified that had these mutations, called SNPs, the team focused on one known as SH3TC2 because it had been linked to other types of Charcot-Marie-Tooth disease. Then they sequenced portions of this gene in family members with mild nerve impairment in their hands or feet. The team discovered two mutations in SH3TC2 that were associated with different forms of nerve impairment, including carpal tunnel syndrome.

"The fact that these studies are coming out at once tells you where the field is moving," says Eric Topol, who studies the genetic basis of human disease at the Scripps Research Institute in La Jolla, California. "It's exciting to see that there are lots of ways to go after what were undiagnosed molecular abnormalities using pinpoint-precision sequencing."

Keep it in the family

The family-based approach has also provided researchers with another way to estimate the rate at which parents pass mutations to their offspring. Galas and his colleagues estimate that each offspring will have 70 new mutations, less than half the number obtained with previous approaches. "It is really important to know this number because it represents the source of all genetic variation we have, for good or bad, for health or disease," says Joseph Nadeau, a human geneticist at Case Western Reserve University in Cleveland, Ohio.

Although whole-genome sequencing might be highly accurate and getting cheaper, it isn't yet within practical reach. Lupski and colleagues, for instance, estimate that their study cost around US$50,000. Less complete forms of sequencing can provide similar information about the genetic underpinnings of diseases such as Miller syndrome and primary ciliary dyskinesia. Last year, scientists used a less intensive method to identify the role of DHODH and DNAH5 in these diseases³.

Ultimately, scientists may realize they don't have to sequence the whole genome, Topol says. "Another way may be cheaper and equally effective; we just don't know yet."