Challenges in Clinical Genomics
Elizabeth Worthey, Ph.D., a director in the Genomic Medicine Clinic at the Medical College of Wisconsin and Children’s Hospital of Wisconsin, shares Dr. Jongbloed’s opinion that WGS is preferable to exome sequencing in general. “If you focus on the exome, nongenic regions aren’t covered. Also, the first exon and some parts of other exons of a gene are often not covered very well.” She also sees challenges in sequencing regions with high GC content and in designing probes for regions that are homologous to other regions of the genome.
“If finances weren’t an issue, everyone would do WGS,” Dr. Worthey says. “In some cases, clinics may resort to using WGS as a reflex test for exome sequencing. If the answer isn’t there, you go to WGS.” Regardless, Dr. Worthey remains optimistic that costs will come down as technology improves.
The Genomic Medicine clinic sees about 20 to 25 new patients each month and performs WGS for about one-third to one-half of them. The current cost is about $5,000 per patient for clinical exome sequencing and analysis, and it is about $17,000 per patient for WGS. “The costs will definitely come down for WGS. For example, the recently released Illumina HiSeq X Ten systems will provide individual centers with two or three times the capacity of what the largest centers in the world can currently process combined.”
Dr. Worthey sees the greatest challenge for clinical genomics in the interpretation phase. “People say that while the sequencing costs $5,000, the analysis costs $1 million. But that needn’t be true—not if the lab has a suitable clinical analysis tool in place.”
The area that needs improvement the most is clinical interpretation, explains Dr. Worthey: “For example, how do you differentiate between all these errors, polymorphisms, causal mutations, etc.? One way is to determine whether a variant has been identified as deleterious previously, or whether it has been seen in many different individuals with different clinical presentations.”
Dr. Worthey points out that there are lots of repositories where this type of data is maintained. “If somebody else has found the same mutation in a patient elsewhere, then that’s what you are looking for, but you won’t know if you don’t have access to their data.”
Ultimately, Dr. Worthey surmises, the problem is data sharing: “If you have been working on breast cancer for many years, are you going to want to put your data in someone else’s database? Ideally, we would develop something where we could share data instantaneously, or there would be a central repository where we could access the data.” But such a repository, adds Dr. Worthey, “would have to be updated frequently for the greatest impact.”
WGS results cannot be interpreted effectively, Dr. Worthey suggests, unless they are compared with all clinical data available from affected patients as well as those who may have the same disease in an early or unusual presentation: “Clinical presentation data can be one page or many hundreds of pages, and there will have to be efforts to better catalogue and curate the data for others to interpret it successfully.”