A Difference of Opinion
Will targeted sequencing remain the standard for diagnostics for the near future? An emphatic, “No,” said Dr. Drmanac. “Targeted sequencing does not give you the right [or complete] answers,” he insisted, making his case for whole-genome sequencing. His company, Complete Genomics is in the business of sequencing whole genomes. He gave three main reasons to support a move toward WGS: genes and regulatory networks are so intertwined and interdependent that contextual interpretation of the sequence data is only possible with whole genome data; all human variation cannot be put on a chip; and we should celebrate the ability to sequence whole genomes.
According to Dr. Drmanac, the technologies available today are scalable and he predicted that in three to four years these methods will make it possible to sequence one million genomes per year.
Regarding the fourth statement, Dr. Drmanac commented that personal genomics is “unstoppable.” It will not displace medical genetics as a field; both medical genomics and medical genetics are needed, as are tests for somatic mutations.
Dr. Drmanac said that WGS information should be acquired as early as possible in a person’s life, with testing done on newborns and prior to embryo selection and implantation in IVF procedures. While the field should focus on what is actionable, that should not limit WGS. He encouraged his colleagues to find all sequence variants in a genome but only report those known to be disease-related.
Currently, Complete Genomics offers sequencing services and provides data only to researchers, who must have IRB consent from patients. In 2012, the company plans to seek CLIA certification, which will enable it to provide data directly to physicians.
In Dr. Hayden’s view, “We have oversold the concept of the genomic revolution.” The promise of the Human Genome Project and genomics has not been fulfilled for the general public, he added. “Don’t oversell the promise of whole-genome sequencing,” noting the excessive hype already surrounding genome-wide association studies (GWAS) and the promise that they will lead to new drug targets and therapies.
In response to statement 1, he questioned what we would do with the information from WGS. There is a “massive information gap” and educational gap, in addition to an absence of clear stakeholders and no reimbursement strategies in place. “Technology is not the problem; delivery is the problem”—and even how to define delivery is a problem. “We are not ready for WGS; for research use, yes, but for patients, no.”
Dr. Hudgins, focused on statement 4 and responded both yes and no. Yes, she feels that personal genomes will be incorporated in the standard of medical care, but how, when, and where are not clear. She vehemently disagreed with the idea that the availability of genomic information will replace medical genetics though.
Personal genomics will change the face of diagnostics, she contended, and instead of relying on phenotype and test results alone, genotype information will be used to support a diagnosis. Dr. Hudgins warned, however, that even those trained in medical genetics are ill-prepared to make accurate predictions based on genetic information related to inheritance of and predisposition to complex disorders. “GWAS are not the whole story,” she added, emphasizing the importance of epigenetics and somatic mutations.
Dr. Veltman based his views on his group’s experience sequencing 500 exomes for clinical research purposes, not patient care, to identify Mendelian disease genes with de novo and inherited mutations related to intellectual disability and blindness. He focused on the issue of protecting patient privacy and safeguarding sequence data. He does not believe that targeted sequencing should be the norm, because one should not assume that a problem lies in only certain genes. Although he “believes strongly in the importance of technologies that have no bias,” he pointed out that “we can implement exome sequencing now.”
Aymé represented the voice of the patients, whose needs, she asserted, should be the focus of the discussion. Those needs “have not changed simply because the technology has advanced,” she said. Patients want to know whether they have a familial disease and whether there is a treatment. “People want to know about their disease, not their disease risk.”
Genomic information should be used only if it would modify the prognosis, concluded Aymé. “I am in favor of developing the scientific aspect of sequencing,” she said, but cautioned against saying that it will improve the quality of care or exposing patients to sequence information unless there is a specific medical reason for doing so.