Genome-wide sequencing: Whole exome sequencing and whole genome sequencing

Genome-wide sequencing refers to two genetic tests, whole exome sequencing and whole genome sequencing, that allow health-care providers to look broadly at your child’s DNA.

Key points

Genome-wide sequencing can examine the entire genetic makeup of a person in a single test. It is used to identify potential genetic causes of your child’s medical condition.
Whole exome sequencing looks at the parts of a person’s DNA that provide instructions for making proteins.
Whole genome sequencing looks at all of a person’s DNA.
Genome-wide sequencing is increasingly used in clinical and research settings.

Introduction

Test

How is genome-wide-sequencing performed?

GWS is performed in molecular diagnostic laboratories using DNA that has been extracted from blood. A blood sample will be drawn from your child, as well as their immediate family members. You will likely be asked to provide a blood sample if you are your child’s biological parent.

While the sequence of DNA between humans is very similar (>99% similarity), there are still millions of differences between individuals that can be detected with GWS. Some of these differences, known as genetic variants, can cause medical conditions. In order to guide the analysis of the differences in your child’s DNA, it is helpful to compare their genetic variants to variants identified in family members who are either unaffected or who have the same or similar medical condition as your child. The laboratory uses your child’s clinical information, family information and current medical knowledge of genetics to evaluate which of the identified genetic variants might be responsible for your child’s medical condition.

Whole exome sequencing

Whole exome sequencing is a test that looks at the parts of your child’s DNA that provide instructions for making proteins. Proteins are very important molecules in the body that help our bodies develop and function. By looking at the order of the DNA that makes proteins, the test will be able to identify if there are any critical proteins missing or not functioning properly in your child’s body.

The exome makes up about 1% of your child’s genetic code. Sequencing this small fragment can be a very efficient and cost-effective way to diagnose rare genetic disorders, as the majority of disease-causing genetic variants occur in this 1% of the genome.

Whole exome sequencing

Whole genome sequencing

Whole genome sequencing looks at all of your child’s DNA. This test is considered more comprehensive than whole exome sequencing as it can detect genetic changes that occur outside of the protein-coding regions in your child’s genome.

After the test

What is reported?

The laboratory will report any genetic variants likely to be associated with your child’s medical condition to the doctor who ordered the test. You and your child will be informed of all test results, and these results will be put into your child’s medical record.

Types of findings reported

Primary findings

A primary finding refers to genetic variants that may explain your child’s medical condition. Different categories of genetic variants may be reported:

Pathogenic: variants that are known to cause the medical condition
Likely pathogenic: variants that are highly likely to cause the medical condition
Variants of uncertain significance: variants for which the impact cannot be determined at the current time

It is possible that the classification of a genetic variant or gene will change over time. The interpretation of your child’s GWS results may also change over time due to new scientific knowledge. As such, it is encouraged that you keep in touch with your child’s doctor to learn of any changes in the classification or interpretation of their results.

Secondary findings

GWS can also identify disease-causing variants in genes that are not related to your child’s primary medical condition. These variants may cause other medical conditions during childhood or later in life and are known as medically actionable secondary findings because there are clear medical recommendations that can be made to reduce the risk that they impact your child’s health in the future.

The laboratory will search for variants in specific disease genes. You may have the option to choose which types of secondary findings you would like to receive. The types of secondary findings available for reporting may vary depending on the laboratory performing GWS.

Whole exome sequencing secondary findings

Potential risks of genome-wide sequencing

Because GWS is performed as a family analysis, the same genetic variants that are identified in your child may also be found in other family members that have provided a sample for testing. This could have medical implications for these other family members.

GWS results may reveal that biological relationships in a family are not as they were reported to the health-care team. This means that the results can show when a child is not biologically or blood-related to their mother, father and other family members who provided a DNA sample. It is important to provide accurate information about the biological relationships and health statuses within your family to prevent an inaccurate interpretation of your child’s GWS results.

Limitations of genome-wide sequencing

GWS does not always lead to a definitive explanation of your child’s medical condition. This is due to the current limitations in medical knowledge and testing technologies.

GWS does not detect all types of genetic variants. When GWS does not identify a pathogenic variant, it does not rule out the possibility that a genetic variant may be causing your child’s medical condition.

With all laboratory tests, there is a small possibility of error or sample failure.

At SickKids

Last updated: June 13th 2022