This new tool offers clinicians the dos and don’ts of genetic testing, what physicians need to know to do it properly 

Clinical use of gene sequencing information has advanced to the point where a team of genetic experts has compiled and issued the Genetic Testing Handbook. The goal of the clinical genome and exome sequencing (CGES) handbook is to provide clinicians—including pathologists and clinical laboratory scientists—with a useful reference tool.

The authors of the Genetic Testing Handbook are Leslie G. Biesecker, M.D., of the National Human Genome Research Institute (NHGRI) in Bethesda, Maryland, and Robert C. Green, M.D., M.P.H., a geneticist who is an Associate Professor of Medicine at Harvard Medical School.

Primer Distills Human Genome Project Technologies for Practical Use

“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,” stated Biesecker, who serves as Chief and Senior Investigator at the NHGRI’s Medical Genomics and Metabolic Genetics Branch, in a press release issued by the National Institutes of Health (NIH).

Pictured above is Leslie G. Biesecker, M.D., Chief and Senior Investigator at the Medical Genomics and Metabolic Genetics Branch National Human Genome Research Institute in Bethesda, Maryland. He is co-author of the Genetics Testing Handbook, now available online at the National Library of Medicine. (Photo in the Public Domain)

Pictured above is Leslie G. Biesecker, M.D., Chief and Senior Investigator at the Medical Genomics and Metabolic Genetics Branch National Human Genome Research Institute in Bethesda, Maryland. He is co-author of the Genetics Testing Handbook, now available online at the National Library of Medicine. (Photo in the Public Domain)

“This primer illustrates how rapidly the use of genome sequencing has moved into clinical practice,” added Eric D. Green, M.D., Ph.D., NHGRI Director. “Its authors lay out an approach for physicians to follow when using these exciting new technologies.”

The authors explained the purpose of their CGES primer in a story published in the June 19, 2014, issue of The New England Journal of Medicine (NEJM).

Diagnostic Indications from Exome Sequencing Data

“Clinicians should understand the diagnostic indications for CGES so they can effectively deploy it in their practices, wrote the researchers in the NEJM article. Because the success rate of CGES for the identification of causative gene variant is approximately 25%, it is important to understand the basis for this testing and how to select the patients most likely to benefit from it.”

The authors further noted that their Genetic Testing Handbook summarizes the technologies underlying CGES and offer insights into how clinicians should order such testing, interpret the results, and communicate the results to their patients.

One assertion made by the authors will be of interest to pathologists and medical laboratory managers performing molecular diagnostics and genetic tests in their labs. In the handbook, the authors write that exome sequencing will be used across a spectrum of medical specialties, not just by geneticists. Exome squencing analyzes sequences of the 1% of protein-coding regions of the human genome and is less expensive than whole-genome sequencing.

Pathologists Can Help Physicians Interpret Exome Sequencing Data

“We think that physicians from different specialties can order this test if they’re willing to take the time and commit to the effort to learn what the test is, what it isn’t, how it works, what it tells you and doesn’t tell you, and how to use the results,” the authors wrote.

Pictured above is is geneticist Robert C. Green, M.D., M.P.H., an Associate Professor of Medicine at Harvard Medical School and practitioner at Brigham and Women's Hospital in Boston He is co-author of the Genetics Testing Handbook, now available online at the National Library of Medicine. (Photo copyright Brigham and Women’s Hospital)

Pictured above is is geneticist Robert C. Green, M.D., M.P.H., an Associate Professor of Medicine at Harvard Medical School and practitioner at Brigham and Women’s Hospital in Boston He is co-author of the Genetics Testing Handbook, now available online at the National Library of Medicine. (Photo copyright Brigham and Women’s Hospital)

What Physicians Need to Know Before Ordering Genetic Tests

They also outlined what physicians need to know to use exome sequencing properly.

1. Whole-genome or whole-exome sequencing technology, for example, is best at detecting single-nucleotide variants, or alternations in sequences of more than eight to 10 base pairs.

2. Because exome sequencing doesn’t cover 100% of the genome, it may not pick up longer variations or repetitions of sequences, or long deletions that are responsible for some genetic disorders.

3. This technology is most promising for patients with rare disorders that may be the result of variants in a single gene. When selecting patients for exome sequencing, physicians should explore family history for signs of similar disorders among relatives and preform an extensive literature search before ordering this test. Informed consent is essential in these cases.

4. Only about 25% of exome sequencing tests result in a diagnosis. Due to the technology’s gaps, however, a negative result—failure to identify a gene variation causing the disease—doesn’t rule out a genetic cause.

5. Identifying a genetic cause for a disease seldom leads to a cure, but can end a search for a diagnosis that is expensive, potentially invasive, and stressful to the patient.

6. Analysis of the results of exome sequencing may produce incidental findings, such as a gene variant unrelated to the patient’s primary disorder. There is also the potential of exome sequencing to identify gene variations that could cause a disease, thus requiring surveillance or treatment for a different condition.

7. Counseling patients and their families about what to expect is essential and challenging because the patient may be disappointed by an inconclusive outcome for such an extensive and expensive test.

In the NIH press release, Biesecker also pointed out that physicians should learn which disorders are appropriate for CGES testing, whether the patient’s family history suggests a single-gene cause, and how to interpret ambiguous results when a test points to a gene or several genes that might be responsible. “If you’re willing to learn those things, I think you can use the test clinically,” he said, stressing that if not, the physician should refer the patient to someone who is willing to learn these things.”

Genetic Sequence Testing to Increase as Physicians Learn How to Use It

Some experts have questioned whether CGES is ready for broad application−whether the medical community’s knowledge of genetics is deep enough to recognize the strengths and weaknesses of the testing. The authors noted in the NEJM article that, ready or not, the technology is here, physicians are ordering genome and exome sequencing for their patients and use will increase. They predicted that about 10,000 CGES tests will be ordered this year and even more next year.

This should be good news for pathologists, who will often be called upon to interpret CGES results, as well as genomics laboratories that do the testing. If Biesecker and Green are correct, pathologists and genomics labs can expect an increase in business.

The Genetics Testing Handbook is available online.

—by Patricia Kirk

Related Information:

New report offers a primer for doctors’ use of clinical genome and exome sequencing 

Report offers a primer for clinical use of genome and exome sequencing

Diagnostic Clinical Genome and Exome Sequencing

Genetics Testing Handbook

Thomas Jefferson University Study Finds Critical Weakness in Commercially Manufactured Exome-Capture Test Kits Used by Some Medical Laboratories

;