Continuing Chrysalis' "5 Questions" series, we reached out to Dr. Robert Green, one of the preeminent experts on the clinical use of whole genome sequencing.  Thank you Dr. Green for your time. 

Question 1: When do you see patients and physicians *routinely* using WGS to inform care? In which lines of care? What are the biggest barriers that need to be eliminated?

In patients with cancer, I see WGS for tumor profiling routinely informing their care within the next few years. Indeed, cancer has been one of the first areas to integrate genomics into treatment plans. We’ll start to see routine exome and genome sequencing of both the tumor and the germline or “healthy” tissue.

Whole genome and whole exome sequencing are already routinely used today in tertiary care institutions to evaluate complicated patients with undiagnosed syndromes. This is successful between 20-70% of the time, depending upon the presentation and while it does not always result in revised treatment, establishing a molecular diagnosis can bring resolution to a diagnostic odyssey and offer reproductive options to family members of an affected patient. Despite the effectiveness of sequencing in these situations, health insurance plans often do not cover it.

Beyond cancer care and undiagnosed conditions, I imagine that as sequencing becomes less expensive, individuals will sequence once and interrogate their genome over time for various reasons including reproductive purposes, cancer predispositions, and cardiac predisposition, to name a few. This information will start to be folded into the medical care of the individual via the different, relevant specialties. Furthermore, I think that there will be an increasing number of parents that want their newborns sequenced as a way to launch them on their lifelong health journey, whether or not there is anything medically wrong with the child at birth.

Ultimately, I think that almost everyone will eventually be able to benefit at some level from having personal sequencing information available to them and to their healthcare providers, and that sequencing and other ‘omics technologies will be well on their way to full integration into the practice of medicine within the next 10-15 years.

As for barriers, the three biggest I see are cost, privacy and the absence of data on clinical utility. Of course, cost is coming down rapidly and I believe that health insurance reimbursement and physician awareness will follow. We, and other groups, are trying very hard to build up the empirical database for justifying when and how to use sequencing information for clinical care.

Question 2: When and how do you envision consumers taking advantage of WGS?

I’m seeing a larger trend where people are seeking health information from a number of directions. They’re seeking it traditionally through their doctors and other healthcare providers, but are also seeking it from sources on the Internet, from each other, through social networking forums, and then through companies.  Seen in this light, sequencing and other ‘omics are a component of a huge movement toward self-quantification and self-empowerment.  Currently, almost all direct-to-consumer genetic testing businesses use genotyping and do not report rare monogenic risk variants. But there are a number of businesses emerging where either panels or whole exomes/genomes are sequenced with input from either the patient’s medical provider or from a medical provider that contracts with the company.  It may be that consumers demand the integration of genomics into healthcare through these various channels and conventional healthcare sources have no choice but to eventually acquiesce.

Question 3: The diagnostic yield of WGS is increasing. Can you highlight one of the more impressive examples of clinical utility?

It’s difficult to find a more impressive example of WGS clinical utility than the story of then six-year-old Nicholas Volker who had a mysterious disease that was preventing him from digesting his food. Genome sequencing resulted in a proper diagnosis – a previously unsuspected diagnosis of a rare autoimmune disease – and pointed his caregivers in the direction of a marrow transplant. This has thus far saved his life and allowed him to enjoy a “normal” childhood after dozens of operations and a downward course that looked like it wasn’t going to end positively. So that’s a very dramatic example that has been highly publicized.

In our hands, we routinely make diagnoses in previously undiagnosed cases that then give families an end to their diagnostic odysseys. It has allowed them to understand what they are facing and make reproductive choices.

Question 4: I know you are deeply involved in the Newborn Sequencing In Genomic medicine and Public Health (NSIGHT) program.  What are the main goals and what, specifically, are you working on?  

The goal of the NSIGHT program is to explore the implications, challenges and opportunities with genomic sequence information in managing a newborn’s care.

There are four NIH funded sites, each with a different research program.  At our site in Boston, we are recruiting the families of healthy and NICU infants into the BabySeq Project, a first-of-its-kind randomized clinical trial designed to examine how best to use genomics in clinical pediatric medicine by creating and safely testing methods for integrating sequencing into the care of newborns.

In order to monitor the long-term impact of the genomic information returned to families, we collect medical, behavioral and economic outcomes over the course of the first year of enrollment. We are examining if there are marked differences between the families who receive genomic information and the families who receive standard of care. We are also enrolling and surveying pediatricians and other doctors involved in the care of enrolled babies to examine how this information may be impacting a child’s medical care. What we learn will help guide the usage and reimbursement for sequencing and other ‘omics.

Question 5: What impact on your behavior/lifestyle did having your own genome sequenced have?

I originally found out from direct-to-consumer genetic testing, and then confirmed on my own sequencing, that I am a factor 5 Leiden carrier, which means my blood clots faster than normal. It has specifically encouraged me to stand up and walk around on long airline flights to try to reduce my risk of deep vein thrombosis.

Beyond that, I have had a chance to dive deep (with help from some smart informaticians that I work with) into the bioinformatics analysis of my genome and to experience first-hand exactly how complex these analyses are.  This has helped me understand and communicate the challenges of implementing sequencing much more clearly.


Robert C. Green, MD, MPH is a medical geneticist and physician-scientist who directs the G2P Research Program ( in translational genomics and health outcomes in the Division of Genetics at Brigham and Women’s Hospital, the Broad Institute and Harvard Medical School. Dr. Green sees patients and conducts empirical research on the medical, behavioral and economic outcomes associated with the implementation of genomic medicine, directing and co-directing the first experimental trials in adults (the MedSeq Project) and newborn infants (the BabySeq Project). He recently co-chaired the Steering Committee of both the Clinical Sequencing Exploratory Research program (18 NIH grants, over 300 investigators), and the Steering Committee of the Newborn Sequencing in Genomic Medicine and Public Health program (4 NIH grants, over 100 investigators) and is a co-investigator on recently awarded Partners site grants within the Electronic Medical Records and Genomics Network and the Precision Medicine Initiative. He is Associate Director for Research of Partners HealthCare Personalized Medicine.