What are whole exome sequencing and whole genome sequencing?

Determining the order of DNA building blocks (nucleotides) in an individual’s genetic code, called DNA sequencing, has advanced the study of genetics and is one technique used to test for genetic disorders. Two methods, whole exome sequencing and whole genome sequencing, are increasingly used in healthcare and research to identify genetic variations; both methods rely on new technologies that allow rapid sequencing of large amounts of DNA. These approaches are known as next-generation sequencing (or next-gen sequencing).

The original sequencing technology, called Sanger sequencing (named after the scientist who developed it, Frederick Sanger), was a breakthrough that helped scientists determine the human genetic code, but it is time-consuming and expensive. The Sanger method has been automated to make it faster and is still used in laboratories today to sequence short pieces of DNA, but it would take years to sequence all of a person’s DNA (known as the person’s genome). Next-generation sequencing has sped up the process (taking only days to weeks to sequence a human genome) while reducing the cost.

With next-generation sequencing, it is now feasible to sequence large amounts of DNA, for instance all the pieces of an individual’s DNA that provide instructions for making proteins. These pieces, called exons, are thought to make up 1 percent of a person’s genome. Together, all the exons in a genome are known as the exome, and the method of sequencing them is known as whole exome sequencing. This method allows variations in the protein-coding region of any gene to be identified, rather than in only a select few genes. Because most known mutations that cause disease occur in exons, whole exome sequencing is thought to be an efficient method to identify possible disease-causing mutations.

However, researchers have found that DNA variations outside the exons can affect gene activity and protein production and lead to genetic disorders–variations that whole exome sequencing would miss. Another method, called whole genome sequencing, determines the order of all the nucleotides in an individual’s DNA and can determine variations in any part of the genome.

While many more genetic changes can be identified with whole exome and whole genome sequencing than with select gene sequencing, the significance of much of this information is unknown. Because not all genetic changes affect health, it is difficult to know whether identified variants are involved in the condition of interest. Sometimes, an identified variant is associated with a different genetic disorder that has not yet been diagnosed (these are called incidental or secondary findings).

In addition to being used in the clinic, whole exome and whole genome sequencing are valuable methods for researchers. Continued study of exome and genome sequences can help determine whether new genetic variations are associated with health conditions, which will aid disease diagnosis in the future.

For more information, please visit the National Library of Medicine and National Institutes of Health website at https://ghr.nlm.nih.gov/primer#testing

What are the benefits of genetic testing?

Genetic testing has potential benefits whether the results are positive or negative for a gene mutation. Test results can provide a sense of relief from uncertainty and help people make informed decisions about managing their health care. For example, a negative result can eliminate the need for unnecessary checkups and screening tests in some cases. A positive result can direct a person toward available prevention, monitoring, and treatment options. Some test results can also help people make decisions about having children. Newborn screening can identify genetic disorders early in life so treatment can be started as early as possible.

For more information, please visit the National Library of Medicine and National Institutes of Health website at https://ghr.nlm.nih.gov/primer#testing

What are the risks and limitations of genetic testing?

The physical risks associated with most genetic tests are very small, particularly for those tests that require only a blood sample or buccal smear (a method that samples cells from the inside surface of the cheek). The procedures used for prenatal testing carry a small but real risk of losing the pregnancy (miscarriage) because they require a sample of amniotic fluid or tissue from around the fetus.

Many of the risks associated with genetic testing involve the emotional, social, or financial consequences of the test results. People may feel angry, depressed, anxious, or guilty about their results. In some cases, genetic testing creates tension within a family because the results can reveal information about other family members in addition to the person who is tested. The possibility of genetic discrimination in employment or insurance is also a concern. (Refer to What is genetic discrimination? for additional information.)

Genetic testing can provide only limited information about an inherited condition. The test often can’t determine if a person will show symptoms of a disorder, how severe the symptoms will be, or whether the disorder will progress over time. Another major limitation is the lack of treatment strategies for many genetic disorders once they are diagnosed.

A genetics professional can explain in detail the benefits, risks, and limitations of a particular test. It is important that any person who is considering genetic testing understand and weigh these factors before making a decision.

For more information, please visit the National Library of Medicine and National Institutes of Health website at https://ghr.nlm.nih.gov/primer#testing

What is informed consent?

Before a person has a genetic test, it is important that he or she fully understands the testing procedure, the benefits and limitations of the test, and the possible consequences of the test results. The process of educating a person about the test and obtaining permission to carry out testing is called informed consent. “Informed” means that the person has enough information to make an educated decision about testing; “consent” refers to a person’s voluntary agreement to have the test done.

In general, informed consent can only be given by adults who are competent to make medical decisions for themselves. For children and others who are unable to make their own medical decisions (such as people with impaired mental status), informed consent can be given by a parent, guardian, or other person legally responsible for making decisions on that person’s behalf.

Informed consent for genetic testing is generally obtained by a doctor or genetic counselor during an office visit. The healthcare provider will discuss the test and answer any questions. If the person wishes to have the test, he or she will then usually read and sign a consent form.

Several factors are commonly included on an informed consent form:

  • A general description of the test, including the purpose of the test and the condition for which the testing is being performed.
  • How the test will be carried out(for example, a blood sample).
  • What the test results mean, including positive and negative results, and the potential for uninformative results or incorrect results such as false positives or false negatives.
  • Any physical or emotional risks associated with the test.
  • Whether the results can be used for research purposes.
  • Whether the results might provide information about other family members’ health, including the risk of developing a particular condition or the possibility of having affected children.
  • How and to whom test results will be reported and under what circumstances results can be disclosed (for example, to health insurance providers).
  • What will happen to the test specimen after the test is complete.
  • Acknowledgement that the person requesting testing has had the opportunity to discuss the test with a healthcare professional.
  • The individual’s signature, and possibly that of a witness.

The elements of informed consent may vary, because some states have laws that specify factors that must be included. (For example, some states require disclosure that the test specimen will be destroyed within a certain period of time after the test is complete.)

Informed consent is not a contract, so a person can change his or her mind at any time after giving initial consent. A person may choose not to go through with genetic testing even after the test sample has been collected. A person simply needs to notify the healthcare provider if he or she decides not to continue with the testing process.

For more information, please visit the National Library of Medicine and National Institutes of Health website at https://ghr.nlm.nih.gov/primer#testing