All of our DNA together is called the genome. About 1 percent of the genome is called the exome; this includes the coding sequences of over 20,000 genes. Most of the DNA sequence changes that lead to disease are present in the exome. Exome sequencing is a type of genetic test that sequences all of our genes to look for the cause of a specific feature or condition. In this section, we explain exome sequencing and the different types of results.
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All of our DNA together is called the genome. About 1 percent of the genome is called the exome; this includes the coding sequences of over 20,000 genes. Most of the DNA sequence changes that lead to disease are present in the exome. While currently scientists only understand a portion of which genes are linked to disease, we continue to learn more every day.
Sometimes a person’s features are strongly suggestive of a genetic condition in general, but one specific gene or a group of genes cannot be pinpointed. In cases like this, it is more effective to sequence all of our genes. This type of genetic test is called “exome sequencing.”
After the exome is sequenced, we will be able to tell if there are any DNA sequence variants. We can then try to determine what sort of effect, if any, each variant has on the gene’s function. For example, is the variant significant enough that it will cause disease? Is the variant neutral or mild enough that it doesn’t really impact the way the body functions?
There are different types of results that can come from exome sequencing.
A positive result means that a genetic test identified a change in a gene that we are confident causes the features in you or your child. Another word that you may see on a report to describe a positive result is “pathogenic”.
A likely positive result means that a genetic test identified a change in a gene that is suspected to cause the clinical findings in you or your child, but there may not be enough scientific information known at this time to say it is definitively positive.
A negative result means that there were no gene changes identified by the testing method that could explain your or your child’s clinical findings.
A variant of unknown clinical significance is a genetic change that, based on the currently available scientific knowledge, cannot be interpreted as pathogenic or negative.
In the future, scientists are likely to discover what these variants of unknown clinical significance mean. Until then, receiving results with a variant of unknown clinical significance can be understandably frustrating as we can’t interpret what the DNA change means for your child or family.
A candidate gene change means that there is a change in a gene that is likely to affect the function of the protein encoded by this gene, but changes in the specific gene have not been linked to any human disease to date. These gene changes are like variants of unknown clinical significance in that we cannot usually act on these changes. As scientists learn more about a candidate gene, this result may be better understood. As other individuals are identified with mutations in the same “novel” genes, a candidate gene may, in time, become a known disease-causing gene.
Keep in mind, genetic testing does not always find an explanation for medical symptoms.
The absence of a positive genetic testing result does not take away an individual’s clinical diagnosis.
Also, a non-diagnostic genetic testing result does not mean that the condition is not genetic. Instead it may mean that the testing completed was not able to identify a genetic cause at this time.*
Since exome sequencing looks at all of our genes, we may also find variants in genes that are unrelated to the reason for doing this test. These are called “secondary findings.”
The laboratory will only report secondary findings that are medically actionable if they are identified in the primary patient. Medically actionable means that a mutation in a specific gene can lead to a medical condition for which there are well-defined medical management guidelines with a potential to improve the outcome. Changes in medical management range from starting a new medication, to undergoing early screening tests.
It is your choice whether or not you and your family want to learn about secondary findings. You can either opt in to get results, or opt out if you’d rather not receive these secondary findings. Unexpected secondary findings are identified in approximately 4-5 percent of families undergoing an exome sequencing test. Please remember, that there is no right or wrong choice about secondary findings. Each family makes their own choice that is right for them. Your genetic healthcare provider will help you through this decision-making process.