All About Genetic Sequencing

All About Genetic Sequencing

You may remember from our previous Science Simplified blog post that our DNA is the foundational instructional manual that our bodies use to function throughout the course of our lives. Our DNA sequence is made up of letters, which are called nucleotides. Did you know that our DNA sequence is made up of 3 billion nucleotides? Everyone has a unique DNA sequence, and in many cases, changes in our nucleotides may have no effect on our bodies and how they function. However, certain nucleotide changes, or variants, can cause disease.

Amazingly, scientists have a way of reading the genetic sequence in an individual to identify variants that may be causing disease. This process is called genetic sequencing. For genetic sequencing, a blood or saliva sample is taken, and DNA is isolated from the sample in a laboratory. You can think of sequencing like reading a book one letter at a time to look for any spelling mistakes.

Genetic sequencing can play a very important role in establishing a diagnosis for a genetic condition such as SLC13A5 Epilepsy. Additionally, genetic sequencing might be useful for family members of those affected by SLC13A5 Epilepsy. SLC13A5 Epilepsy is an autosomal recessive condition, meaning those who inherit two abnormal copies of the SLC13A5 gene will have this severe form of epilepsy. Carriers are people who only have one abnormal copy of the gene. While they may be healthy and have no symptoms of SLC13A5 Epilepsy, there could be a chance they could have a child with SLC13A5 Epilepsy. Genetic sequencing can be used to determine if family members of those with genetic conditions are carriers.

What type of test results can be expected from genetic sequencing?

Positive test result 

  • A positive test result means that a genetic variant has been identified as the cause of disease

Negative test result

  • A negative test result means that a genetic cause for disease was not identified using the test that was performed
  • A negative result does not rule out the possibility that an individual has a disease-causing genetic variant
  • In some cases, additional genetic testing may be considered

Uncertain test result

  • An uncertain result means that a genetic variant was found, but the meaning of the finding is not known.
  • As new information about variants and genes becomes available, uncertain test results may be re-interpreted at a later date. The results could end up being re-classified as either negative or positive.

If you are interested in learning more about results from a genetic sequencing report, please be on the lookout for a future Science Simplified article which will cover this topic in greater detail!

Types of Genetic Sequencing

There are several types of genetic sequencing tests available, and each has its own unique advantages, limitations, and reasons for use.

Single-gene Testing

Targeted single-gene tests look for genetic changes in one specific gene. Genes are sections of DNA that provide our body with instructions for making a specific type of protein. (For a review on proteins, check out our previous Science Simplified blog post.) There are about ~22,000 genes in our body, and each makes a certain type of protein.

Remember how our DNA sequence is 3 billion letters long? In some cases, it doesn’t make sense to read all those letters if you know exactly what you are looking for! That would be like reading an entire cookbook when you really only want to look at one recipe.

A few reasons why single gene testing might be performed are below:

  • To confirm a genetic diagnosis in someone who has symptoms of a specific condition or syndrome, such as Cystic Fibrosis.
  • To test family members of someone who is known to have a specific variant in a gene to see if they have the same condition. For example, single gene testing might be used to test whether a sibling of someone with a known SLC13A5 variant also has the SLC13A5 variant.

Gene Panel Testing

While single gene testing can be very useful in some cases, in other instances, you might need to read more of the DNA sequence to find out whether or not there are any disease-causing variants present. As mentioned above, single gene testing can be used to test family members of those with SLC13A5 Epilepsy. However, single gene testing probably wouldn’t be used to diagnose a new case of SLC13A5 Epilepsy. That is because SLC13A5 is just one of hundreds of possible genetic causes of epilepsy. To diagnose a new case of SLC13A5 Epilepsy, a gene panel test might be a better option.

Gene Panel tests look at a certain number of genes that cause a set of symptoms. For example, epilepsy panels look at genes that we know cause epilepsy, and SLC13A5 might be a gene on that panel! Importantly, the SLC13A5 gene might be sequenced on other types of panels, including those for other types of neurological disorders such as cerebral palsy. This is because there might be overlap with some of the symptoms.

Whole Exome Testing

Whole Exome Sequencing is a more extensive genetic sequencing test that involves sequencing all ~22,000 genes, which are the protein-coding regions of the genome (also called the exome). While 22,000 genes sound like a lot to sequence, the exome makes up only 1-2% of all DNA material in a human being! Despite the relatively small proportion of the entire DNA sequence, the exome is where most disease-causing variants are found.

A few reasons why whole exome testing might be performed are below:

  • To try to determine a genetic cause for an individual’s symptoms when the symptoms are complex and do not fit a specific disorder or syndrome
  • To try to determine a genetic cause for an individual’s symptoms when previous genetic testing, such as a gene panel, have come back negative

Whole Genome Testing

Whole Genome Sequencing is the most comprehensive genetic sequencing test that is available. As mentioned above, the 22,000 genes that make up the exome represent only 1-2% of all DNA material in a human being. The entirety of the DNA material in an individual is called the genome. Much of the genome does not have a known purpose or relationship to disease. Scientists are currently researching the purpose and function of the genome in order to make this information more useful in the future. Since this test is relatively new, it is typically not offered clinically, and may only be available if the person being sequenced is part of a research study.

With tests such as whole exome or genome sequencing, there is the possibility of discovering “secondary or incidental findings.” Secondary or incidental findings are disease-causing variants that are unrelated to why the individual was tested. For example, an individual who undergoes whole exome sequencing for suspected epilepsy may be found to have a disease-causing variant in a gene that causes an increased risk for cancer. In many cases, individuals can opt out of learning about secondary findings.

Because whole exome and whole genome tests are sequencing many more nucleotides than a targeted single gene or gene panel test, there is a greater chance that the test results in an uncertain test result, which can be unsettling and confusing.


Genetic sequencing can be an important tool for diagnosing genetic conditions, which in some cases, can affect the medical management of symptoms or provide treatment options. In addition, genetic sequencing can be helpful for family members of people affected with genetic conditions, as it can help determine who in the family might be at risk of being a carrier. There are several different types of genetic sequencing tests which each have their own benefits and limitations. For those who are interested in genetic sequencing, it might be helpful to discuss options with a genetic counselor, who can help you understand the benefits and risks of different types of tests.

For more information on genetic sequencing, check out the resources below:

NORD Genetic Testing Video

MedLine Plus Genetic Testing

This article was written by Baergen Schultz, a genetic counseling graduate student at the University of Pennsylvania. Baergen completed an internship with TESS Research Foundation as part of our partnership with the Orphan Disease Center at the University of Pennsylvania.

Figures were created using

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