Genome Technology Enters the Mainstream

Genome technology has gone mainstream. Once deemed “exotic,” according to Brigham and Women’s researchers, the technology is now being used more and more to diagnose rare or puzzling disorders that clinicians suspect could be genetic in origin.

BWH reps say that so far, several thousand clinical genome and exome sequencing (CGES) tests have been ordered for patients across the country and thousands more are expected in coming years. “CGES is quickly moving from research laboratories into clinical medical practice, across all specialties,” reps say.

But with any new technology comes uncertainty. That’s why researchers at BWH published a new article in the June 19 edition of the The New England Journal of Medicine which outlines what physicians need to know about genome technology in order to use it properly.

“This is a transformative moment in the history of medicine as we begin to integrate genome sequencing into the care of patients,” said Dr. Robert C. Green, co-author of the paper and a medical geneticist and co-director of the Personal Genomics Consultation Service at Brigham and Women’s Hospital (BWH). “While our focus in this article is on the use of sequencing in cases where diagnosis is difficult, the sequence is just the beginning. We can expect these technologies to help us transition our entire approach in medicine to more personalized and preventive care.”

The authors agree that physicians must understand that exome sequencing can’t answer all questions and isn’t appropriate for all patients. For example, the authors point out that sometimes identifying a genetic cause won’t necessarily lead to a cure. That said, in these cases, exome sequencing may still be useful because it can “end an expensive, potentially invasive and stressful, diagnostic odyssey.”

The authors also note that counseling patients and their families about what to expect is essential, but it’s also challenging because after a test that is an extensive and expensive test as this, if there’s an inconclusive outcome, a patient may be disappointed.

Other issues brought up in the paper include:

· While these technologies are sometimes referred to as whole-genome or whole-exome sequencing, they don’t cover 100 percent of the genome or exome. Because of the way the target DNA sequences are gathered and assembled, not all of the DNA can be sequenced and the technique is best at detecting single-nucleotide variants, or alterations in sequences of no more than 8-10 base pairs. It may not pick up longer variations or repetitions of sequences, or long deletions that are responsible for some genetic disorders.

· Patients for whom the technology is most promising are those with rare disorders that seem to be the result of variants in a single gene. Physicians should explore family history—the presence and pattern of similar disorders among relatives—and should carry out an extensive literature search before ordering exome sequencing. Informed consent is essential.

· Exome sequencing may not provide a diagnosis. On average, about 25 percent of such tests identify a gene variant that causes disease; most come up empty. Because of the technology’s gaps, however, a negative result doesn’t necessarily rule out a genetic cause for the disease.

“The technologies that were used for the Human Genome Project are now distilled down to practical tools that clinicians can use to diagnose and, hopefully, treat diseases in patients that they couldn’t treat before,” said Dr. Leslie G. Biesecker, of the National Human Genome Research Institute. “It’s come much faster and developed more quickly and become more useful clinically than I think any reasonable person would have suggested just 10 years ago. At that time, I don’t think anybody would have taken you seriously if you had said that in 2014, tens of thousands of patients would be getting clinical genome and exome sequencing.”