Cross-posted (in a slimmed-down form) on the Wellcome Trust blog.
There are thousands of rare genetic diseases, ranging from the widely-known (such as Huntington’s disease, an adult-onset brain disorder) to the obscure (such as fibrodysplasia ossificans progressiva, a disease affecting less than one in a million people, in which the patient’s muscles are slowly replaced with bone). While individually rare, these diseases collectively create a tremendous burden of suffering: childhood-onset single-gene disorders affect nearly four children in every thousand live births, and are responsible for more than 10% of paediatric hospital admissions.
Previously, finding the mutations that cause these rare diseases was a lengthy process, relying on a technique called linkage analysis. Firstly, DNA samples were collected from large families affected by the disease. Secondly, these samples were examined at thousands of highly variable sites across the genome, to look for markers that were always found in patients but not in their healthy family members. Finally, researchers needed to comb through the dozens or hundreds of genes close to these 'linked' markers to look for mutations that might be disease-causing.
This whole process takes time, money, and more than a little luck. In addition, for certain classes of genetic disease - those that have only been found in small families, or are caused by genetic changes that arise spontaneously in patients rather than being inherited from either parent - linkage analysis is impossible. That means that while this technique has successfully deciphered the genetic basis of thousands of rare genetic diseases, many remain unexplained.
Finding the underlying mutations for these diseases is of far more than just academic interest. For patients and their families a full genetic diagnosis can provide a sense of closure after years or decades of enduring medical tests with no clear answers. In some cases identifying the underlying gene can provide important clues about the underlying mechanism of the disease, and perhaps even point to potential therapies. However, we also shouldn't underestimate the raw scientific value of these studies: every gene we link to a rare Mendelian disease increases our understanding of the ways genes work together to build a human being.
Over the last few years, rapid advances in DNA sequencing technology have begun to provide a cost-effective alternative to linkage analysis. Rather than first looking for the regions of the genome that are linked to the disease, cheap sequencing offers a simple, brute force solution: look at all of the genes in a patient’s genome, see which ones contain a likely damaging mutation, and then investigate those genes to see which is most likely to cause the patient’s disease.
New sequencing technologies have resulted in a dramatic drop in the cost of reading a person’s DNA. However, it’s still expensive to sequence their entire genome - all six billion letters of it will currently set you back somewhere in the order of US$20,000 (£12,200). Fortunately, most rare diseases (around 80%, by some estimates) are caused by mutations found in a relatively small fraction of the genome: the pieces that code for proteins, known collectively as the exome.
These pieces of protein-coding sequence are scattered across the genome, but only make up less than 2% of its total length. Using an approach called sequence capture - in which tiny DNA probes are used to pull out the protein-coding regions in a patient’s DNA, letting the remainder wash away - it is possible to extract and sequence only these regions. The small size of an exome means it can be sequenced from a patient for just a few thousand pounds - in many cases, substantially less than the cost of a series of single-gene tests.