Thus far, whole genome sequencing has been limited to identifying genes linked to so-called Mendelian disorders, in which mutations in a single gene cause the disease. Eventually, Lupski, Hood, and others aim to move on to more complex diseases, such as Alzheimer’s. “There are various ways to turn a common disease into a rare one–you start with families that have more severe forms of common disease, or earlier onsets,” says George Church, who leads the Personal Genome Project at Harvard. “I think almost every disease has rare [variants].” It was this type of approach that led to the identification in 1993 of the Alzheimer’s risk gene APOE4, still the strongest genetic risk factor known to date. Now, thanks to cheap sequencing, the ability to scan the genome in its entirety will allow a much broader and more thorough search.
Lupski’s family gives a potential example of how genes tied to rare disorders may shed light on more common ones. Two of the scientist’s siblings who carried one of the genetic mutations linked to Charcot-Marie-Tooth had signs of carpal tunnel syndrome, a common disorder often caused by repetitive movements. “That’s a very common disease and now we have insight into it,” says Church. “I think there will be lots of cases where you identify a gene in one person in a family, and then start asking questions about the phenotype of family members with only one copy.”
Church and others say the two studies signal a new trend in human genetics research. Over the last few years, microarrays designed to cheaply screen human genomes for common genetic variations linked to common, complex diseases have mostly picked up variants with only a mild effect on disease risk. The bulk of the genetic causes of these ailments remains a mystery, and a growing number of scientists believe this disease risk lies in rare variants only detectable with whole-genome sequencing.
Lupski, who as a medical geneticist still sees patients once a week, won’t be able to offer them whole-genome sequencing in the next year or two. “I don’t want people to think everyone can have this diagnosis, or that having a diagnosis means there is a cure,” says Lupski. “But we can start using the technology more and more for gene discovery.”
But cost-wise, personal genomes may not be far off. For example, Bird at the University of Washington says that a comprehensive genetic screen for inherited nerve diseases costs about $15,000. Researchers estimate that Lupski’s genome cost about $50,000. And Complete Genomics, a startup in California that sequenced the family in Hood’s study, will soon offer bulk sequencing services for about $20,000 a genome, with a $5,000 price tag not far behind.