Skip to main content
Premium Trial:

Request an Annual Quote

Clinical Genetics Experts Offer Advice for Implementing Diagnostic Exome, Genome Sequencing


NEW YORK (GenomeWeb) – In an effort to provide guidance to the growing number of institutions that are implementing clinical exome and genome sequencing for inherited disease diagnosis, a group of clinical genetics experts from the US and Canada has developed a set of recommendations, taking into account advice and experience from physicians, lab workers, scientists, genetic counselors, and — last but not least — patients and their families.

The guidelines, published in Genetics in Medicine last month, were spearheaded by researchers at the Hospital for Sick Children in Toronto and the Children's Hospital of Philadelphia and resulted from two "Clinical Genetics Think Tank" meetings in 2014 and 2015, each with about 50 participants. They included representatives from institutions well known to be early adopters of clinical genomics, such as the University of Washington School of Medicine, Baylor College of Medicine, the National Human Genome Research Institute, Johns Hopkins University School of Medicine, Stanford University School of Medicine, and Harvard Medical School.

The effort was initiated by Sarah Bowdin, an associate professor of pediatrics at the University of Toronto and a staff physician at the Hospital for Sick Children, and Ian Krantz, a professor of pediatrics and genetics at the University of Pennsylvania and director of the Individualized Medical Genetics Center at CHOP, who both several years ago were establishing clinical exome and genome sequencing programs at their respective institutions. "We realized that we were basically struggling and grappling with very similar issues," Krantz told GenomeWeb. "In some areas, we were going in divergent directions, and in many other areas, we were sort of reinventing the wheel."

The recommendations are meant to smooth the path for those setting out now to establish clinical genomics. And while they remain a work in progress and there are still "a lot of questions that are yet to be answered," he said, "it was important to identify the issues and some common ways of thinking about them and dealing with them."

The document was also meant to provide a different view than policy statements from the genetics professional organizations, such as the American Society of Human Genetics and the American College of Medical Genetics and Genomics, according to Bowdin. "It was really meant to be from practitioners and clinicians and researchers and laboratorians working in the trenches on this topic," she said, as well as "family members dealing with this on a day-to-day basis." The group did include individuals deeply involved with ASHG and ACMG, though, who helped make sure that they did not replicate work already done by those organizations.    

The White Paper covers five areas of the clinical workflow in detail, presenting challenges and providing recommendations for each: the pretest process, including selecting patients for testing and determining insurance coverage; pretest education for patients and providers; phenotyping of patients to assist with the interpretation of their genomic test results; sequence data interpretation and clinical reporting; and post-test patient care, including the return of primary and secondary findings, and managing genomic data over time.

While the published document is the result of discussions among the group, it does not mean complete consensus was reached on all issues. Participants disagreed on broad questions, Krantz said — for example, some favored panel testing over genome-wide approaches, while others thought exome and genome testing was ready for broad adoption — as well as on details of the approach.

For example, he said, there was discussion on how much sequence coverage should be required, what types of variants should be reported, and how broadly data should be shared between institutions. Krantz was particularly involved in a subgroup that focused on phenotyping, and "there was a lot of back and forth about what type of clinical information should be collected, whether it should be very focused, or whether we should be trying to capture broad clinical pictures to share in common databases."

But the group also found answers, and patient families often contributed to this, in particular regarding questions about pretest counseling and post-test care. "If there was any area where clarity was brought, it was often by the patients or parents saying 'actually, this is the thing we value the most, we don't care about X,Y,Z, we care about A,'" Bowdin said.

For example, families made it very clear that they would prefer to have two separate appointments to discuss test results, one for primary findings related to the patient's condition and another to hear about secondary findings, she said.

The group included a handful of patient families who had received testing in the past and had been very vocal about their experience, either because they had benefited from the primary and secondary results or because they were distressed by them. "We tried to balance by having both families who felt that the approach to genomic testing needed to be better regulated and other families who thought this was the greatest thing since sliced bread," Krantz said.

Overall, one area that still needs the most development is post-test patient care, Krantz said. While pretest counseling, phenotyping, sequencing, and variant interpretation will likely become more standardized over time, he said, there is still debate about what types of results should be returned, particularly to pediatric patients.

Beyond that, open questions remain on how genomic data can be integrated into electronic health records and how they can be used longitudinally. Genomic testing "is different from most other tests in that the data is vibrant — it's not like you are screening a single gene and getting an answer and moving on," he said. "How do we make [the data] queryable from one year to the next, how do we flag things that are important that were not flagged initially, and how do we make it accessible to the families and to their primary care doctors? Those are huge issues that we're struggling with."

Longitudinal use of the data will maximize the value of genomic testing, Bowdin said, which will be appreciated more in countries with a single-payer system, like the UK, than countries with a fragmented healthcare system, like the US. "If you ask an insurance company, they have almost tunnel vision: 'How much does this test cost to get the primary result?'" However, over a patient's lifetime, genomic testing will likely have other uses and could save payers costs in the long run, she said.

Ultimately, the recommendations are laying the groundwork for population-based genome screening for disease prevention, which Krantz and others believe will be the future of exome and genomic sequencing.

He and Bowdin are thinking about reconvening the group that developed the current guidelines in order to discuss, for example, the use of genome sequencing in newborn screening or screening of adult populations. "The idea of using this technology in healthy individuals is a huge topic that needs to be addressed," Krantz said. "Is that something that should be considered? What are the limitations? What would be the advantages of doing that, and what infrastructure would be needed to support that?"

To prepare for this use of the technology, other medical specialties will need to get involved, including those where genomic testing is already increasingly used, such as neurology, gastroenterology, immunology, rheumatology, and cardiology, but in particular pediatrics. Pediatricians "should be thinking about what their guidelines should look like in five years' time for predictive or secondary findings," Bowdin said. "One of the big areas that we know nothing about right now is whether there is any harm to returning secondary variants to children, and that's going to be an ongoing topic of research."

In parallel, a "huge educational push" in training non-geneticist clinicians is required, Krantz said, "because there are not enough geneticists to manage this workload, so the specialists and primary care doctors have to get comfortable using this kind of data as well." Genetics and genomics are already becoming more integrated into medical school curricula, he said, so newly-minted doctors will be more at ease using such data, but there will likely be a big gap between them and currently practicing physicians.

But clinical geneticists are also not immune to change. "Our field is changing dramatically," Krantz said. "The types of patients that we are being asked to care for and manage are much more generalized than they were in the past. We're not just managing individuals with rare Mendelian traits or rare metabolic diseases — we are now being asked to manage patients with [conditions] that are falling under the genetics and genomics umbrella because there are tests available that can help to diagnose these patients that were not available 10 years ago."

Another issue warranting further scrutiny is quality standards for the interpretations of genomic data around the world. Bowdin cited the example of a colleague in Hong Kong who has been seeing patients from other parts of China who came to see him with poorly interpreted exome or genome sequence reports and asking for preimplantation genetic diagnostic testing to avoid passing on conditions to their children that they may in fact not have.

The problem is not confined to China, Bowdin and Krantz said, but also occurs in North America, where some labs return reports directly to consumers that contain either inaccurate interpretations or results that are misinterpreted by patients. "There is a lot of damage control that goes on currently," Krantz said.