Some might question whether genome sequencing - and its cut-down version exome sequencing - are ready to move from the lab to the clinic. Experts warn that physicians do not know enough about genetics to understand the strengths and weaknesses of such tools.
But clinicians have already ordered several thousand tests - particularly to help with cases of rare childhood diseases - suggesting that, ready or not, the technology has already entered the realm of general medical practice.
The transition has been sooner than anyone expected, and the use of clinical genome or exome sequencing (CGES) is likely to increase, say Drs. Leslie G. Biesecker and Robert C. Green, two leading scientists from the US who have sketched out what doctors need to know in order to use the new technology effectively. Their "primer" is published as a report in the New England Journal of Medicine.
Dr. Biesecker, chief of the Medical Genomics and Metabolic Genetics Branch of the National Human Genome Research Institute (NHGRI) in Bethesda, MD, says 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."
He says the technology has arrived and developed faster, and has become more useful in the clinic than any reasonable person might have expected 10 years ago, when it was unlikely "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."
Dr. Green, who leads an NHGRI-funded CGES project and several other translational genomics research projects at Brigham and Women's Hospital and Harvard Medical School in Boston, MA, says: "This is a transformative moment in the history of medicine as we begin to integrate genome sequencing into the care of patients."
Primer focuses on cases that are difficult to diagnose
He explains that while the focus of the primer is on the use of CGES 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."
Exome sequencing is a "cut-down" or abridged version of genome sequencing and has identified gene variants that cause or contribute to many diseases.
Genome sequencing looks for differences - at the level of individual "letters" or base pairs in DNA - between a patient's genome and a reference genome to find "variations" or "mutations" that may cause disease or affect risk of disease. Genome sequencing targets 3 billion base pairs of the human genome.
Exome sequencing is a "cut-down" or abridged version of genome sequencing. It carries out the same comparison but on a much smaller amount of DNA - the 1-2% that codes for proteins and accounts for around 20,000 genes.
Sometimes the quickest - and cheapest - way to look for variants or mutations that cause disease is to look only at the exome.
In 2013, the NEJM published an NHGRI-funded study that showed how exome sequencing identified the genetic cause of disease in about 25% of patients.
Exome sequencing has identified gene variants that cause or contribute to many diseases, including epilepsy, cardiomyopathy, metabolic disorders, cancer, amyotrophic lateral sclerosis (ALS, or Lou Gehrig's disease), Charcot-Marie-Tooth disease, mental retardation and other neuropathies.
Physicians need to understand what CGES can and cannot do
However, there is a danger that because the new technology is so powerful that clinicians may be under the impression that it will answer all their questions. The authors warn that physicians must understand it cannot do that, and it may not be appropriate for all patients.
The primer sets out what clinicians need to know and do to use CGES properly. For instance:
- While sometimes called "whole-genome" or "whole-exome" sequencing, the technologies do not cover 100% of the genome or exome. The technology works best when looking for alterations in sequences comprising eight to 10 base pairs - so may not pick up longer variations or repetitions that may be responsible for genetic disease.
- The technology seems most suited to patients with rare disorders caused by variants in single genes. Doctors should look at family history for similar disorders and carry out extensive literature searches before ordering CGES for patients. Also, they should make sure to obtain informed consent.
- Do not expect exome sequencing to provide a diagnosis. Most tests produce no results - only 25% of them on average find a gene variant that can cause or increase risk of disease. Conversely, a negative result does not mean there is no genetic cause.
- In most cases, identifying a genetic cause does not lead to a cure. But this does not necessarily mean the test was a waste of time and cost - it may have prevented the patient having to undergo invasive and stressful alternative diagnostic procedures.
- The test may uncover gene variants for diseases that are not related to the patient's primary disorder.
- It is essential that patients and their families have counseling. This can prepare patients for the possibility of disappointment, as the test - which can be expensive - may not help doctors reach a diagnosis or provide a conclusive answer.
The authors say it is not clear whether insurers will pay for all or some of the costs of CGES tests, although Dr. Biesecker says he has heard reports from some labs that insurers are reimbursing for them.
In a final comment, he says physicians thinking about using CGES should learn which diseases the tests can and cannot handle, what family histories suggest a single-gene cause, and how to interpret ambiguous results, and urges:
"If you're willing to learn those things, I think you can use the test clinically. If you're not willing to learn those things, you probably shouldn't be ordering the test, and you probably should refer the patient to somebody who is willing to learn these things."
Meanwhile, Medical News Today recently learned how researchers from Oxford University in the UK developed a computer algorithm to help diagnose rare genetic disorders in children from photographs. Writing in the journal eLife, the researchers describe how the method looks for structural matches between faces in photographs and facial features characteristic of certain conditions, such as Down syndrome, Angelman syndrome and progeria.