Next-Gen Sequencing: Expanded Genetic Testing in the Real World

Marshall L. Summar, MD; Brendan C. Lanpher, MD; Sean E. Hofherr, MD

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September 15, 2014

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Editor's Note: Marshall L. Summar, MD, is Chief of the Division of Genetics and Metabolism and the Margaret O'Malley Chair of Molecular Genetics at Children's National Medical Center in Washington, DC. He is an internationally recognized expert in translational studies with an emphasis on developing clinical applications based on molecular genetics research. In an interview for Medscape, Dr. Summar spoke with Brendan C. Lanpher, MD, Clinical Director in the Division of Genetics and Metabolism, and Sean E. Hofherr, PhD, Director of Molecular Genetics at Children's National. Their discussion focuses on real-world practical aspects and possible pitfalls of expanded genetic testing in this environment of rapid technological advances.

Expanding Horizons in Genetic Testing

Dr. Summar: I am here with Dr. Brendan Lanpher and Dr. Sean Hofherr. Dr. Hofherr is Director of the Molecular Genetics Program at Children's National Medical Center, and Dr. Lanpher is Clinical Director in the Division of Genetics and Metabolism at Children's National.

The topic today is next-generation testing, with some "dos and don'ts" and practical pointers. There has been a lot of talk, chatter, advertising, and hype over the past few years about next-generation expanded DNA testing, and I would like to discuss the practical aspects of these tests.

Brendan, what do you see as the current role of expanded genetic testing?

Dr. Lanpher: The current world of next-generation sequencing and expanded molecular genetic testing is very exciting, but also very daunting. It allows us to test for things that we have never been able to test for before. But it also allows us to find things that we are not looking for in more effective ways than we have ever had before.

Dr. Summar: Could you elaborate on that?

Dr. Lanpher: The most exciting new trend in genetic testing is that with the newer technology -- the next-generation sequencing -- you can test a large number of genes with one blood sample, up to and including whole-exome sequencing, in which you test nearly all of the currently known genes with a single test.

The problem is that we all have a huge amount of genetic variation. Knowing and determining whether a variation that we find is disease-causing or not gets more and more challenging with the increasing number of variations found in a single test. Correlating a test result with a patient's phenotype -- the patient's actual clinical situation -- is critical. Having a well-defined, well-thought-out, and well-described phenotype is very important for the laboratory to give you the best interpretation possible.

Dr. Summar: By "phenotype," do you mean a detailed description of the patient?

The Critical Importance of Preparation

Dr. Lanpher: Exactly. Another downside is that we find things that we didn't set out to find, which can be confusing and anxiety-provoking for both families and physicians. When you are testing for a large number of genes, you will inevitably find variations. Sometimes, these variations are in genes that can be medically important, such as susceptibility genes for cancer, cardiac disease, or other later-onset diseases. Sorting out whether the patient is at risk can be very challenging.

Dr. Summar: That sounds very time-intensive from a clinical standpoint.

Dr. Lanpher: It is. It takes a lot of time to counsel patients and families both before and after the test. It's very important before you embark on next-generation genetic testing that the patient and family receive very detailed genetic counseling about the potential and the limitations of the test. There is no single test for all diseases. There is no perfect test.

Patients may not appreciate the complexity of these tests. It's very important for a family to have a good sense of that complexity before they go down that road. Our genetic counselors spend a lot of time with families before we do this kind of testing. We hope that families have a good understanding of the potential for complex results before they receive them. You can only prepare people so much, but it is very important that they have that time with us before and after the test results come back so that they are as prepared as possible.

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