When Is Genome Sequencing Advisable?

Awareness of whole genome sequencing (WGS) is greater than ever, especially among patients—and demand is growing equally fast.¹ But not every patient needs WGS and it’s often up to providers to guide the selection, completion, and interpretation of appropriate testing for each person and condition.

What is driving the rapid increase in WGS utilization? When is this broad-spectrum look at patients’ genomes necessary? And what happens when even genomics fails to put a name to a mystery condition?

To sequence or not to sequence?

“WGS is primarily used for patients and families with rare diseases that are likely to be caused by a single genetic change,” says Caroline Wright, a professor of genomic medicine at the University of Exeter. “It is particularly useful in cases such as childhood developmental disorders where the individual change could lie in one of thousands of genes, so testing them all at the same time is much more efficient.”

Although few of these disorders have cures, many have treatments that can be offered once a diagnosis is established. Even for those that don’t, putting a name to the condition may increase prognostic accuracy, influence family planning recommendations, or even give patients access to therapies they might not otherwise receive.

But WGS isn’t for everyone. “If the patient’s clinical picture seems to be pointing toward a well-known condition, then targeted sequencing approaches or specific tests that can be performed using other methodologies might make more sense in that situation,” says Jessica Thomas, an assistant professor of clinical pathology and genomic medicine at Houston Methodist Hospital. “If the patient has gone through a diagnostic odyssey already and has not received a diagnosis, then they might move on to whole exome or genome sequencing.”

Wright also highlights that common conditions like type 2 diabetes or cardiovascular disease involve many different contributing factors. “Most genetic changes associated with these diseases have a tiny effect and could not be used to diagnose a condition alone,” she says. “Those individuals are not good candidates for WGS at the moment.”

Who, what, and when?

Both Wright and Thomas agree that requests for WGS are increasing. To explain this phenomenon, Wright points to growing patient and provider awareness, expanding access to genomics, and improvements in affordability and coverage.

“I think it’s somewhat driven by need in that the more targeted approaches are not answering the question for every patient,” Thomas says. “But it’s also driven by ordering providers who may move straight to the ‘big guns’ rather than begin with more targeted evaluations.” This can lead to problems: increasing the cost of testing for patients who may not have needed WGS, extending wait times for those who do, and even introducing the possibility of misdiagnoses or incidental findings. To help alleviate the burden of unnecessary testing, clinical laboratory professionals should be able to advise on scenarios that may—or may not—warrant WGS.

“Refer to guidelines from professional societies and make sure you have a good awareness of the types and levels of testing that are available,” Thomas recommends.² “Then, ask questions to find out what testing has previously been done and work with the patient’s physicians to determine the best options for next steps. Bear in mind that some tests may not be reimbursable by insurance, so make sure you do right by the patient in a financial sense as well.” If patients cannot obtain coverage for necessary testing, Thomas recommends looking into their eligibility for clinical trials or other programs that offer WGS free of charge.

Wright can attest to the success of this approach. “I have been lucky enough to have worked on the UK-wide Deciphering Developmental Disorders study, which used exome sequencing to try to find genetic diagnoses in children with severe undiagnosed developmental disorders, for the last 14 years,” she says.³ “The study has made a huge difference to patients, yielding around 5,500 individual diagnoses—many of which changed patients’ clinical management and treatments due to the diagnosis—and also discovering around 60 novel disorders so far.”

Diagnostic hurdles

Typically, patients eligible for WGS have already undergone other forms of testing without receiving a diagnosis. But what happens when even genomic sequencing fails to yield answers?

“At the moment, the best bet is to make sure the data are shared and reanalyzed in future so that researchers can discover new causes of disease and this new knowledge can be implemented diagnostically,” says Wright. “There may be other things that can be tried in specific cases—for example where the patient’s symptoms are really specific for a particular condition and more targeted functional investigation, such as RNA sequencing or methylation analysis, could be informative.”

In many cases, WGS fails to uncover a diagnosis, but yields variants of unknown significance (VUS). “That is quite a controversial issue and different labs have different guidelines about VUS reporting,” says Wright. “We generally only recommend reporting VUS when there is likely to be a clinical action that can be taken to resolve the variant, such as genetic testing in a relative (to determine inheritance) or further testing of the patient. There are a large number of VUS, and reporting all of them is unlikely to be practical.”

Commonly, labs will report any VUS uncovered in genes associated with the patient’s phenotype.⁴ This allows providers the option of issuing a provisional diagnosis and acting on the likely cause of their patient’s symptoms until more data confirms or precludes the variant’s pathogenicity. Some labs narrow the field by omitting VUS entirely and reporting only variants with confirmed pathogenicity; others broaden it by including candidate gene VUS in their reports, which allows providers to re-evaluate and reinterpret the patient’s data with updated knowledge.

What’s next for WGS?

“More of it!” says Wright. “There will be a huge amount of sequencing done for clinical and research purposes and it’s really important that the data are shared to maximize the benefits for everyone. I expect long-read sequencing will also become more widespread as the cost comes down and accuracy goes up, which will increase the types of variants that can be detected.”

As more genomes are sequenced and analyzed with cutting-edge technologies, new genotype-phenotype associations will be documented, which increases the likelihood that future patients will receive definitive diagnoses. This expanding body of knowledge may also open up new treatment options, more accurate prognoses, and a better understanding of family members’ risk of developing or passing on genetic conditions.

“The sky’s the limit,” says Thomas. “It’s just going to take a little time to get there.”

References:

1. Phillips KA, Douglas MP. The global market for next-generation sequencing tests continues its torrid pace. J Precis Med. 2018;4:https://www.thejournalofprecisionmedicine.com/wp-content/uploads/2018/11/Phillips-Online.pdf.
2. Souche E et al. Recommendations for whole genome sequencing in diagnostics for rare diseases. Eur J Hum Genet. 2022;30(9):1017–1021. doi:10.1038/s41431-022-01113-x.
3. Deciphering Developmental Disorders. Welcome to DDD! https://www.ddduk.org.
4. Vears DF et al. Reporting practices for variants of uncertain significance from next generation sequencing technologies. Eur J Med Genet. 2017;60(10):553–558. doi:10.1016/j.ejmg.2017.07.016.