Published online 14 September 2010 | Nature | doi:10.1038/news.2010.465

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Physicians are turning to genomic tools to diagnose puzzling conditions.

Whole-genome sequencing of patients' DNA is already helping physicians make treatment decisions. JAMES KING-HOLMES / SCIENCE PHOTO LIBRARY

It may be small-scale and without fanfare, but genomic medicine has clearly arrived in the United States. A handful of physicians have quietly begun using whole-genome sequencing in attempts to diagnose patients whose conditions defy other available tools.

As hospitals and insurers battle over coverage for single-gene diagnostic tests, and the US Food and Drug Administration cracks down on the products of personal genomics companies, a growing number of doctors are relying on the sequencing of either the whole genome or of the coding region, known as the exome.

"If one hospital is doing it, you can be sure others will start, because patients will vote with their feet," Elizabeth Worthey, a genomics specialist at the Human and Molecular Genetics Center (HMGC) of the Medical College of Wisconsin in Milwaukee, said at the Personal Genome meeting at Cold Spring Harbor Laboratory in New York last weekend.

In May 2009, the genetic-technology provider Illumina, based in San Diego, California, launched its Clinical Services programme with two of its high-throughput genome analysers. The company now has 15 such devices dedicated to this programme.

Illumina provides the raw sequence data attained from a patient's DNA sample to a physician, who passes it on to a bioinformatics team, which works to crack the patient's condition. However, Illumina is working to develop tools to help physicians navigate genomes and identify genes already associated with diseases, as well as novel ones.

So far, the company has sequenced more than 24 genomes from patients with rare diseases or atypical cancers at the request of physicians at academic medical centres. The standard US$19,500 price tag is typically covered by the patient, by means of a research grant, or with the help of private foundations, although one patient is currently applying for insurance reimbursement.

Steering treatments

Such efforts are having a direct effect on treatment decisions. For three years, physicians at the Children's Hospital of Wisconsin in Milwaukee had struggled to treat a child whose intestines had become swollen and riddled with abscesses. At the age of 3, he had more than 100 separate surgeries and his colon was later removed, but his doctors were stumped.

They called on Worthey and her colleagues at the HMGC. The team obtained a completed exome sequence for the child and used in-house tools to identify the disease culprit as the protein XIAP, which inhibits a programmed-cell-death pathway called apoptosis. XIAP has a role in the immune system and is conserved across organisms including primates, flies and frogs.

The hospital's lab was then able to show that the child's cells were more sensitive than normal to apoptosis, and the gene is known to play a role in the immune system. On the basis of this diagnosis, the physician recommended a bone-marrow transplant in June 2010. By mid-July, the child was eating his first meal.

Such work demands substantial resources. That child's case took a team of 30, says Worthey, and included a 12-person bioinformatics team, three sequencing technicians, five physicians, two genetic counsellors and two ethicists. The hospital is already working on a handful of other whole-genome sequences, and plans to be analysing 90 per year by 2014.

During the past year, familial whole-genome and exome sequencing has identified gene variants with a role in disease at a rate of two to three per month. One major programme, the Undiagnosed Diseases Program at the National Institutes of Health in Bethesda, Maryland, has received more than 3,000 enquiries and reviewed 1,192 medical records, diagnosing 15% of the cases they have accepted. As of this month, the programme has also completed 59 exomes from 15 families. Thomas Markello, a geneticist and paediatrician on the project, says that the team has confirmed one genetic cause for a disease, and has a dozen new candidates to be validated.

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Whole-genome sequencing is also affecting treatment choices for atypical cancers. Richard Wilson, director of the Genome Sequencing Center at Washington University in St. Louis, Missouri, spoke at the meeting of a 39-year-old woman who was thought, from a bone-marrow biopsy, to have acute promyelocytic leukaemia (APL).

However, when she was given the standard diagnostic test for the disease, this failed to demonstrate the expected exchange of a large piece of chromosomes 15 and 17, which causes two genes to fuse together.

But when Wilson and his colleagues sequenced and analysed cancerous tissue in the bone marrow, they found that a small chunk of chromosome 15 had popped out and been inserted into chromosome 17, fusing the two affected genes in a novel way. As a result, the woman was prescribed a drug known to improve survival in patients with APL. "We were able to assist oncologists in making an effective diagnosis and treatment, which — not trying to hype it at all — saved the patient's life," Wilson said.

Tim Aitman, a molecular geneticist at the UK Medical Research Centre's Clinical Science Centre in London, says that cases in which whole-genome sequencing has directly benefited the patients involved are still rare. "The view is these are anecdotes and one-off occasions," he says, "but it is inescapable that within the next 10 and 20 years that will become much more routine."