Empowering knowledge? (Image: Laurent/Maya/BSIP/Science Photo Library)

IT’S not quite the long-heralded $1000 genome, but it is getting close. For the first time, doctors have begun rolling out large-scale sequencing of the protein-coding portion of people’s genome. This could help to identify the causes of conditions such as congenital deafness and some learning disabilities. More common diseases are expected to follow. The hope is that such sequencing will improve treatments, determine how a person might respond to a drug and possibly even predict disease before it starts.

Although analysis of genetic-code changes known as single nucleotide polymorphisms can identify common variants associated with disease, these cannot be used for diagnosis because most only raise the risk by a few per cent. And although doctors use genetic screening to identify versions of single genes known to cause diseases like cystic fibrosis, other conditions such as blindness can be caused by mutations in many genes. “It’s very hard for the clinician to pick the right gene,” says Leslie Biesecker of the National Human Genome Research Institute in Bethesda, Maryland.

In an ideal world, people’s entire genomes would be mapped to find a potential root cause of a particular disease, but that is very expensive and the technology isn’t ready for the clinic. Instead, doctors are turning to the exome – the 1.5 per cent of the genome that encodes proteins. Sequencing takes about 10 days, and some companies already offer it for just $1000.


Last year, a clinic in the Netherlands became the first to start offering clinical exome sequencing to people on a large scale. So far they have examined 262 exomes from people with conditions including intellectual disabilities, blindness and cancer. They were able to match a genetic cause to a diagnosis in about half of the cases of blindness, and in 15 to 25 per cent of the other diseases studied.

Making an accurate diagnosis doesn’t necessarily lead to a cure, but it’s a start, says Marcel Nelen of Radboud University Medical Centre in Nijmegen, who presented the results at the European Society for Human Genetics (ESHG) meeting in Nürnberg, Germany, last month.

“If you focus on intellectual disability patients, they often have a long history of being hospitalised before a diagnosis. Exome sequencing can reduce that time,” he says.

It can also be important for parents who have a child with a medical condition. They often want to understand what is wrong and how it happened. For example, mothers may worry that it had something to do with their pregnancy or labour. Knowing about a genetic mutation also means that subsequent babies can be tested in the womb for the same mutation.

Rare conditions are just the start. Researchers are already homing in on the genes underlying some forms of heart disease. Exome sequencing could potentially be used to diagnose all kinds of disease, says Biesecker. Although many conditions may be simpler to diagnose by reading symptoms, we are rapidly nearing a point at which exome sequencing could be used to spot diseases before their effects are felt, or predict how people might respond to drugs or vaccination.

Before that happens, the accuracy of the technique needs to improve. Just this week, Mary Emond at the University of Washington in Seattle and her colleagues took a step in that direction. They announced that they had used exome sequencing to identify people with cystic fibrosis who are at high risk of infection with the bacterium Pseudomonas aeruginosa– associated with worse lung health and survival (Nature Genetics, DOI: 10.1038/ng.2344).

As sequencing improves, people will face the possibility of other unsavoury gene variants being spotted unexpectedly as a result of sequencing. Biesecker has been using exome sequencing to study the genetic causes of atherosclerosis – in which arteries harden. He told the ESHG meeting that of the 572 people he has sequenced so far, genes with strong links to cancer were discovered in 10 of them. If sequencing becomes widespread, genetic counsellors will be needed to help people deal with these kinds of findings – although this isn’t necessarily a bad thing. “These people have a predisposition to cancer,” says Biesecker. “We’re simply changing it so that they need counselling before they develop cancer, rather than afterwards.”

Of the 572 people sequenced so far, 10 had genes with strong links to cancer