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Whole Exome Sequencing

  • A type of genetic sequencing performed from blood or saliva samples
  • For people with a family history of disease or who are searching for a diagnosis to explain symptoms
  • The next step is discussing the results with your provider
  • Involves Genetics and the Genetic & Cancer Prevention Program

Dr. Saquib Lakhani, assistant professor of pediatrics at Yale School of Medicine, is also clinical director of the Pediatric Genomics Discovery Program, which relies on exome sequencing to serve its patients.

Photo by Robert A. Lisak

Overview

If you have a health condition that is difficult to diagnose, or a family history of medical problems, your doctor might recommend genetic sequencing for additional clues. Whole exome sequencing is a type of genetic sequencing increasingly used to understand what may be causing symptoms or a disease. Genetic testing has already been used for a long time in some health areas, such as cancer diagnosis and prenatal screening.  

"Genetics," "DNA," and "exome" (explained below) are terms that appear more frequently in health care news as personalized medicine inches closer to reality. (The goal of personalized medicine is to prescribe medicine and treatment that is tailored to your genetic makeup.) Exome sequencing has the potential to play a big role. 

Technical words aside, the process of exome sequencing is straightforward. "It's helpful to think of a person's genome as an instructional manual that directs the body's processes," says Saquib Lakhani, MD, clinical director of the Yale Medicine Pediatric Genomics Discovery Program (PGDP). "You can think of chromosomes as chapters within the manual; genes as the sentences, and DNA as individual letters. Exome sequencing is like running a spell check program." 

At Yale Medicine, this "check" is done at the Yale Center for Genome Analysis, a CLIA-certified laboratory, by experts who specialize in sequencing patient exomes from samples of saliva or blood. They then provide the results to geneticists, bioinformaticians, and researchers, who comb through the data looking for unusual genetic mutations. Usually, a patient's physician will then collaborate with this group to interpret results and relay information back to the patient. 

At present, exome sequencing is only available by referral from your doctor or for patients involved in clinical trial studies. As exome sequencing becomes more common, though, its costs will likely drop and its availability will increase. This type of test could join the ranks of routine genetic tests already widely available now.   

What is the exome?

The human genome, the term for an individual's complete set of DNA, is made up of three billion "letters" (called base pairs). These are, in turn, crammed into 23 pairs of thread-like structures called chromosomes, which are inside every cell in the body. 

A particular sequence of letters (or DNA) form a gene. DNA provides instructions for cellular processes in the body. However, not all DNA does this. Researchers have established that only between 1 to 2 percent of all genes provide instructions, or code, for proteins, which are the building blocks of cells. This "coding" portion of the genome is called the exome. 

Though it's possible to sequence or map out a person's entire genome, it's costly and requires a great deal of computer storage to house such large amounts of data. Because researchers estimate that 85 percent of all disease-causing genetic variants can be found in the exome, whole-exome sequencing is more commonly done. 

Am I a candidate for whole exome sequencing?

Given that whole exome sequencing is still a relatively new diagnostic technique, doctors are judicious in selecting which patients may benefit from having it done. Research has shown that exome sequencing could detect genetic mutations related to birth defects and developmental delays. So, patients who have a family history of disease or are searching for a diagnosis to explain symptoms may be able to avoid unnecessary diagnostic tests by undergoing exome sequencing.

What are the risks and benefits of exome sequencing?

There are many potential benefits of exome sequencing. For example, if your doctor learns that you have a genetic variant strongly associated with heart disease, he or she may advise a proactive treatment plan that focuses on heart healthy foods and lifestyle habits. A newborn baby or child with a genetic birth defect can be given specialized treatment early in life. 

The risks of exome sequencing are mainly psychological and should be discussed with health care providers and carefully considered. Because your entire exome will be sequenced, experts may discover what are called "secondary findings." This may uncover risk for a disease that was not originally suspected, or variants that may predispose you to other diseases, like cancer. In most cases, a patient can choose to opt out of learning about secondary findings.