Boston—“Genetics currently sucks at predicting the types of diseases that will kill most of the people in this room,” complained Massachusetts General Hospital geneticist Daniel MacArthur. MacArthur’s talk, “All Genomes Are Dysfunctional,” opened the second day of the Fourth Annual Consumer Genetics Conference. He was a member of a panel focusing on how genomic information is actually being used by consumers and physicians. Why does genetics currently suck at making predictions? Among other reasons, simply knowing that everyone with a disease carries a particular gene variant doesn’t mean that everyone with that variant has the disease.
For example, 80 percent of the people being treated in clinics for the hereditary iron overload disease hemochromatosis are homozygous (have two copies) for a specific gene variant. However, out in the world, less than 1 percent of people who are homozygous for that variant actually have the disease. Other genes are likely counteracting the effect in disease-free people or perhaps the healthy carriers have not encountered some particular environmental trigger.
In order to turn genomic information into predictive medicine, MacArthur repeated the rallying cry heard constantly at the conference, “Sequence all the genomes!” Sequencing hundreds of thousands more genomes and linking them to the electronic health records of the sequenced individuals will enable researchers to figure out which gene combinations actually produce disease. “To fully understand one genome we need to compare it to data from hundreds of thousands of genomes,” said MacArthur. He urged that all of this information be publicly available, perhaps deposited in the National Center of Biological Information’s ClinVar database.
No Genomic Angst
What do consumers do with genomic information and how does it affect them psychologically? Not much in either case, reported social scientist Cinnamon Bloss from the Scripps Translational Science Institute. Her group has completed a study in which several thousand volunteers took a genotype screening test that gave them some probabilistic disease risk information. The volunteers were tested for disease anxiety before and six months after the test. The study also queried the participants if they had made any changes in their lives in response to the test results. Bloss found no changes in baseline in terms of anxiety or positive changes in diet and exercise. However, at six months some 25 percent had shared their results with their physicians, and that figure increased to 36 percent after one year. A large majority of the participants also claimed to find the results useful and understandable.
Bloss noted that a Food and Drug Administration (FDA) panel asserted in 2011 “that certain types of genetic tests... should not be used without the involvement of a physician or a genetic counselor.” Why? According to Bass, nearly all of the actual data finds “no measured adverse impacts of direct-to-consumer genetic testing.” Besides, Bloss pointed out, it’s time to consider models for providing genetic information to consumers and patients that do not involve genetic counselors and physicians since most physicians are not able to interpret genetic testing results and there are too few genetic counselors relative to consumer demand for testing. One questioner suggested that the FDA regulators seemed to be caught up in “genetic testing exceptionalism,” pointing out that people can take HIV and pregnancy tests at home which yield some very consequential results.
Designer Babies for All?
That was the question in the next talk by Diana Bianchi, the executive director of the Mother Infant Research Institute at Tufts University. She focused on the blindingly fast uptake of breakthrough non-invasive testing for fetal trisomy diseases, the condition of having three copies, rather than the norm of two copies, of a given chromosome. The classic trisomy disease is Down’s syndrome, which is characterized by three copies of chromosome 21, though there are also rarer trisomies of chromosomes 18 and 13. The new fetal trisomy tests rely on the fact that 10 percent of the cell-free DNA circulating in a pregnant woman’s blood comes from the fetal placenta.
The tests will be a year old this month and already 70,000 women around the world have taken advantage of them; 50,000 in China, and 20,000 in the United States. The new tests are much more accurate than the old standard of care, involving serum screening, ultrasound, and invasive surgeries to obtain fetal cells for checking. The false positive rate is 0.2 percent and, according to Bianchi, there are no known examples of false positives negatives. In fact, some Chinese testing companies are so confident of the test results they offer to pay $30,000 to any woman who continues her pregnancy in reliance on the test and subsequently gives birth to a baby with Down’s syndrome.
More non-invasive fetal genetic testing is on the way, including tests for Rhesus D, fetal sex, sickle cell, and thalassemia. Bianchi pointed out pregnant women have a tremendous interest in direct-to-consumer fetal testing, citing the popularity of the PinkorBlue fetal gender test. Available over the counter in drugstores, that particular test can identify fetal gender as early as seven weeks into a pregnancy.
The National Institute of Standards and Technology’s Marc Salit loves measuring things. He is heading up a public/private collaboration, the Genome in a Bottle Project, to produce reference materials for validating various methods of doing whole genome sequencing. The goal is to produce extremely well characterized reference genomes that can be handed over (in a bottle) to sequencing companies and research labs to check how accurately their processes are working.
Physicians Hate Consumer Genetics
Or at least they are really, really skeptical is the take-away message from the two person panel on the physician’s perspective of genome data. The first panel member was Harvard Medical School physician and researcher Issac Kohane who warned consumer genetics enthusiasts to be wary of the “incidentalome” lurking in current genomic data. Kohane coined that word to highlight the proliferation of false positives in genome research. For example, in a recent article in the journal Genetics In Medicine, Kohane notes that the published genome of the co-discoverer of the double-helix structure of DNA James Watson reports that he is homozygous for gene variants previously documented to cause two different congenital diseases. In this case, Watson has inherited from both parents variants for Usher syndrome and Cockayne syndrome.
People who suffer from Usher syndrome typically become deaf and blind in early childhood, and those afflicted with Cockayne syndrome fail to grow, age prematurely, and have abnormally small heads. The 84-year-old 1962 Nobelist in Physiology or Medicine does not appear to suffer from either syndrome. As cited above, Watson’s case illustrates again the fact that knowing that everyone with a disease carries a particular gene variant doesn’t mean that everyone with that variant has the disease. This is because there is tremendous redundancy built into our genomes. As Kohane explained it, “one thing going wrong is not enough to take us down. That would not be evolutionarily robust.”