Exome Sequencing Q&A with Dr. Fatemi and Julie Cohen

Can you explain exome sequencing in layman’s terms?

The majority of genetic diseases are caused by mutations located in the exons, which are the regions of genes that code for protein.  Exons, known collectively as the exome, make up about 1.5% of the genome, which in total consists of over 20,000 genes and 3 billion DNA letters. Traditional genetic testing analyzes only one or a few specific genes at a time. In contrast, exome sequencing is a much broader test targeting the exons of nearly all 20,000 genes simultaneously, eliminating a huge amount of guesswork as well as saving time and money.

What is the cost of exome sequencing?

Currently, several clinical laboratories offer exome sequencing for about $7,000 – $9,000. It was double that a year ago, and originally took millions of dollars to sequence the human genome.  Many predict that the cost of exome sequencing will eventually drop to under $1,000.

How many patients at Kennedy Krieger have an unknown diagnosis?

There are thousands of patients at the Institute for whom exome sequencing could be applied. In the neurogenetics clinic, only 10 to 20 percent of our patients are able to be diagnosed with a genetic cause.

What are the benefits of using exome sequencing to find a diagnosis?

If it is a known disease, we can give a prognosis and, possibly, treatment. It also allows for family planning for the extended family. Sometimes parents have one child and want to know the chances that this will happen in the next child. We can also tell siblings their chances of having a child with the same disorder.

Can you use exome sequencing to predict diseases or disorders?

Yes, and that is the scary part. When you look at all the genes, you may see genes that cause brain disease or liver disease, so we might identify a variant that will give a patient a higher probability of lung cancer. So others may use exome sequencing as a predictor for the likelihood of developing cancer, for example, but we are not using it for that purpose.

Are there any risks or downsides to using exome sequencing?

Yes, and that’s why we are so careful with this right now. We may find things we don’t want to know. For example, we could identify that an 18-month-old patient has a great risk for developing Parkinson’s disease at 65. Right now, patients sign a consent form if they are under 18 years old, and the lab will not report a gene that has an implication for later in life. There are also ethical and legal issues: What if we are looking for risk factors for epilepsy and we find a risk factor for cancer? What if we find 2,000 new genes in the future—who is responsible for going back and looking at a patient’s exome?

What implications does exome sequencing have for the future of diagnosing diseases and disorders?

It could have broad implications. The future depends on how far society is going to take this. It could change the way doctors diagnose. Instead of having so many tests, we will have one single test. Right now we test for a single disease, and then move on to the next one by trial and error. In the future, we may also be able to identify which genetic makeup has a better chance of recovering from certain diseases or disorders, such as traumatic brain injury, and have a fuller outcome.