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HudsonAlpha's 'Elective Genome' for Healthy Individuals Adds to Emerging Field


NEW YORK (GenomeWeb) – The HudsonAlpha Institute for Biotechnology has launched an 'elective genome' test for healthy individuals, called Insight Genome, that also allows participants to enroll in a clinical research study of genetic risks for common diseases.

Insight Genome, which is self-paid and costs approximately $7,000, and has a turnaround time of about 90 days, is currently available through the Smith Family Clinic for Genomic Medicine, which is affiliated with HudsonAlpha, as well as the University of Alabama at Birmingham School of Medicine. The cost includes a clinical whole-genome sequencing test, a separate pharmacogenetic test, and pre- as well as post-test visits with physicians and genetic counselors.

"We should be calling these 'elective genomes' because just like elective surgery, there is not a medical indication. The patient wants it, the doctor orders it, and the insurance company is definitely not paying for it," explained David Bick, medical director of the Smith Family Clinic and chief medical officer at HudsonAlpha, who will present results from a pilot study of the new test at the American College of Medical Genetics and Genomics annual meeting in Phoenix next week.

The launch comes at a time when more and more providers are starting to offer clinical exome and genome sequencing services not only to patients with rare undiagnosed diseases but also to seemingly healthy individuals wanting to take a peek at their genetic makeup, with the hope that they will gain information that will enable them to predict, and prevent, future disease or harmful effects of drugs.

At the upcoming ACMG meeting, for example, the topic of sequencing healthy individuals will be discussed in a dedicated session with representatives from Harvard's MedSeq project, Illumina, Baylor Miraca Genetics Laboratory, HudsonAlpha, and the National Human Genome Research Institute.

Also, new commercial entities have sprung up in recent years that offer individuals clinical-grade exome or genome sequencing tests prescribed by a doctor, among them Genos, a spinoff from Complete Genomics, and Veritas Genomics, cofounded by Harvard Medical School professor George Church.

The practice is not without controversy, however, as some medical experts say we do not know yet how to interpret genomes of healthy individuals, there is no evidence such screening tests provide any benefit, and they generate false-positive results leading to unnecessary and sometimes invasive follow-up tests. "It's premature and inadvisable as a clinical service," said James Evans, a professor of genetics and medicine at the University of North Carolina at Chapel Hill, and the editor in chief of the journal Genetics in Medicine.

Howard Jacob, executive vice president for genomic medicine at HudsonAlpha, said that the Insight Genome grew out of the clinical whole-genome sequencing service the Smith Family Clinic has been offering for several years now for patients with rare undiagnosed or misdiagnosed genetic diseases. "People kept asking: What about me? I don't have a rare undiagnosed disease, [but] having your DNA is so important. It's a family history, it's quantitative," he said.

In response to such requests, about a year ago, he and his colleagues started to develop a similar test for individuals without rare diseases. "We decided to figure out if we could provide something that is of value to people who are healthy," he said.

Patients obtaining a referral for the service from their physician need to come to the clinic for a genetic counseling session where they learn what kind of information the test can provide, and what protections the Genetic Information Nondiscrimination Act offers. That visit also includes a physical exam and a discussion of the patient's medical records, including their personal and family medical history. Prior to their visit, patients may provide additional medical information that may not be in their record through a checklist. As part of the informed consent, they also need to decide whether they want to receive any carrier status results, secondary findings for adult-onset treatable conditions, or secondary findings for adult-onset non-treatable disorders.

After their blood is drawn, the DNA is extracted and sequenced to 40x depth in HudsonAlpha's Clincial Services Laboratories using Illumina HiSeq X sequencers. Part of the blood sample is sent to genetic testing firm Kailos Genetics in Huntsville, Alabama, which runs a separate PGx test that analyzes 149 loci in 38 genes implicated in the metabolism of 89 drugs. The reason for this is that some variants in pharmacogenetically important genes are difficult to obtain from next-gen sequencing, Jacob explained.

For the analysis of the whole-genome data, the HudsonAlpha team only looks at known disease genes, and only genes that have some connection to the patient's personal or family medical history. For those genes, it reports pathogenic and likely pathogenic variants, as well as variants of unknown significance. This approach, Jacob said, is similar to the one HudsonAlpha takes to analyze the genomes of patients with rare diseases.

In one patient who had a history of kidney stones, for example, they found a variant in a gene implicated in this condition. "But if he had had no history and no family history [of kidney stones], we would never even have wanted to think about reporting that variant," Bick said.

For secondary findings in genes that are not related to the patient's phenotype, or a disease that runs in his family, the team only reports pathogenic or likely pathogenic variants and no VUS. In addition, they report some pharmacogenetic variants that are not part of the Kailos test.

Patients have the option to participate in a clinical research study that focuses on common diseases and has a separate consent. For that, the researchers will report information on about 9,000 SNPs they selected based on a number of criteria, among them that they were discovered in genome-wide association studies with more than 1,000 participants and, in most cases, that they have been replicated in more than one ethnic group. "That gives us some higher confidence that the variant, and that association, are real," Jacob said. For three diseases — myocardial infarction, macular degeneration, and rheumatoid arthritis — the team will provide especially in-depth information that is developed by its educational outreach group.

Patients will receive those results on an app, and the goal of the study is to see how they and their physicians use them, compared to how they use family history today, and what type of information they are most interested in. For example, if patients don't want to learn about risk variants for Alzheimer's disease, they can include them, but sometimes those variants also have implications for cardiovascular disease, which a patient may want to learn about.

The researchers also recommend updating the results once a year, maybe as part of a physical exam, against the most recent scientific and medical literature. "The idea is to build that framework for what we think is the right way of doing genomic medicine, which is, you keep looking at it, you keep updating it," Jacob said.

Next week at the ACMG, Bick and Kelly East, a genetic counselor at HudsonAlpha, are scheduled to report results from the first 24 patients who received the Insight Genome test. Seven of them received information "that was relevant to their care today," Jacob said, and a significant number had pharmacogenetic variants that alter their drug response.

In one case, Bick said, they found changes in two genes — TMPT3A and NUDT15 — that alter metabolism of thiopurine drugs, which are used in the treatment of acute lymphoblastic leukemia and autoimmune disorders, such as Crohn's disease. If this patient were to develop one of these diseases and were treated with these drugs, the dosing would need to be adjusted to avoid bone marrow suppression, he said.

Some pharmacogenetics panels in use today include only one of the two genes, he added, so they would not detect both the changes he carried. "You could get part of the answer, but by doing a genome, you can get the whole answer," he said.

The results also have potential implications for the patient's relatives, he added, and having the genome will allow for new results to be included going forward. "In the future, we'll be able to look back at this guy's genome and see if there is anything else medically that's relevant, but also, we'll be able to see whether the field of pharmacogenetics has made progress," he said. "As an individual, I would certainly want my physician to be as up on what drugs are good and bad for me as possible."

But not everyone agrees that pre-emptive whole-genome testing in healthy individuals is a good idea. For one, doctors do not know yet how to interpret genome results in this patient population. "We just don't have a body of experience, literature, data, in order to do that effectively," said UNC's Evans. "Indeed, we have very good evidence that we are not at all good at interpreting genome-scale sequencing in healthy individuals."

Offering such a test as a clinical service is premature, he said. "You end up doing harm to people when you do tests that are not indicated, because you don't know how you interpret them, and you ultimately, inevitably, interpret them wrong. That leads to downstream tests and downstream care that is oftentimes invasive or burdensome."

While there have been anecdotal reports of how whole-genome sequencing has benefited healthy individuals, he said, those results oven involved over-interpretation of variants. "You should not practice medicine by such rare cherry-picked anecdotes," he said.

Pre-selecting genes for interpretation based on a patient's medical history is certainly helpful to refine the interpretation, but still would not justify analyzing an entire genome. "Except in the rarest of cases, it's not going to suggest that a genome sequence would be indicated, or worthwhile, or really anything but misleading, given our significant challenges and demonstrated inability to interpret genomes in healthy individuals," Evans said.

"If you take a family history, and you see clear-cut indication that somebody needs sequencing of this gene or that gene, well, you should sequence this gene or that gene," he said. "Doing whole-genome sequencing in these people is, at best, overkill."

Also, while performing whole-genome sequencing on healthy individuals for research studies is a good idea, offering it as a clinical test for a significant price might not be the best way to recruit research participants, he added.

As for offering whole-genome sequencing as an elective medical test, Evans said it is as inadvisable as offering whole-body MRI scans, which generate vast numbers of false positives. "MRI can be wonderful and lifesaving. And in the same way, our ability to sequence genomes is a wonderful and miraculous thing, and when used right, can benefit people. But to use it indiscriminately is as silly as using whole-body MRIs indiscriminately."

Offering a test because patients ask for it is not a good enough reason, he said, just like doctors should not give antibiotics to patients with viral upper respiratory infections just because they demand them. "People may ask for it, people may want it, but I will tell you that responsible medicine does not involve dispending everything that people want," he said.

Bick said that just like other elective tests, the Insight Genome has upsides and downsides. On the upside, in a very small percentage of people, it may turn up a secondary finding about an adult-onset disorder that the patient had no idea about, for example.

"We often get hammered on this stuff because it's out of the ordinary, [and people say] we should not be doing this," Jacob said. "But medicine is filled with these types of elective procedures. And we're just saying that we think that if people want to take this as an elective genome, why not do this. And we will all agree that with time, knowledge then allows it to become more and more beneficial."