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Next-Generation Genome Sequencing Identifies Disease Genes


By Kevin Davies

March 10, 2010 | Two studies published this week show convincingly that whole-genome sequencing of individual patients or affected families can reveal the one gene out of some 25,000 in the human genome bearing a deleterious mutation.

Writing in the New England Journal, Baylor College of Medicine’s Jim Lupski, Richard Gibbs and colleagues show that by sequencing the whole genome of an affected individual—in this case Lupski himself—it is possible to identify the rogue gene for a recessive disease by filtering the variations in the coding genes to focus on just those that are novel and predicted to cause a significant phenotypic change.

Meanwhile, in Science, researchers at the Institute of Systems Biology (ISB) identified the gene for a rare Mendelian disorder called Miller syndrome by sequencing a family of four (parents and two children).

Jim Lupski is a widely respected clinical geneticist who played a key role in the interpretation of the genome of James Watson, published in 2008. Lupski is an expert on structural rearrangements in genetic disease, documenting one of the first such cases back in 1991. That disease was Charcot-Marie-Tooth (CMT) disorder, a peripheral neuropathy, which happens to affect Lupski and other family members.

Lupski disclosed the results of his personal genome sequencing project in a talk late last year at the American Society of Human Genetics convention. Despite studying CMT for more than two decades, Lupski could not attribute his disorder to any of the dozens of known CMT genes. Finally, Baylor genome chief Richard Gibbs offered to conduct a whole-genome sequencing experiment.

After the sequencing, using the SOLiD platform from Life Technologies (estimated cost less than $50,000), Lupski had to narrow the search. No copy number variants were found to affect any of the dozens of known CMT genes. But by focusing on coding variants in 40 known neuropathy genes, the errant gene, SH3TC2, was identified. One of the mutations appears to be associated with carpal tunnel syndrome.

While the Baylor team concedes that whole-genome sequencing was probably not essential in tracking down the faulty genes in this particular case, they conclude: “As a practical matter, the identification of rare, heterogeneous alleles by means of whole-genome sequencing may be the only way to definitively determine genetic contributions to the associated clinical phenotypes” in complex diseases.

Miller Time

The ISB study published in Science employed the human genome sequencing service of Complete Genomics. The results were among the first 14 genomes that Complete Genomics undertook. The two children in the family suffered from a rare craniofacial disorder called Miller syndrome, as well as a lung disorder called ciliary dyskinesia, which resembles cystic fibrosis. Neither parent had these conditions, suggesting the possibility that recessive mutations in two unrelated genes could be responsible.

Complete Genomics sequenced the four genomes to a depth of 51x to 88x, and called around 90% of the bases in each genome. Variations in four genes were consistent with recessive inheritance of rare variations. In a separate study on the same family, another Seattle group led by Michael Bamshad and Jay Shendure recently reported one of those genes, DHODH, as the cause of Miller syndrome. And mutations in one of the other candidate genes, DNAH5, were previously associated with ciliary dyskinesia. “We are convinced that this new kind of analysis, family sequencing, will be a remarkably powerful scientific and medical tool in the future,” said David Galas, senior vice president of ISB.

Complete Genomics CEO Cliff Reid said his goal was “to provide large-scale complete human genome sequencing as a service that would enable our customers to make medically-relevant discoveries. We are delighted that ISB is already making breakthroughs of that caliber from its first study using our service. This is the type of positive disruptive influence that we want our technology to have on medical research.” 

Question Time

In a commentary accompanying the Lupski et al. New England Journal study, Yale University and Howard Hughes Medical Institute investigator Richard Lifton said the rapid progress in whole-genome sequencing raises profound medical and societal questions:

“Who will benefit from comprehensive sequencing? When in a person’s life should sequencing be done? How should we deal with the many variants of uncertain clinical significance? How should we interpret changes found outside of genes? How should we effectively communicate the results to patients in ways that will improve health without inducing neurosis?”

Such questions are taking on added urgency as the trickle of published human genomes is on the brink of turning into a torrent. Another question is whether the early success in identifying Mendelian disease genes via whole genome sequencing will be repeated as these and other groups tackle other examples.

Editor’s Note: Jim Lupski is a plenary speaker at CHI’s XGen Congress in San Diego, March 15-19, 2010.

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