by Ditsa Keren

Identify Rare Genetic Diseases with GeneDx

Identify Rare Genetic Diseases with GeneDx
GeneDx, Inc. is a global leader in genetic and genomic testing, providing expertise and personalized support that enables patients and healthcare providers to answer important questions and make informed health decisions. In this interview, Executive Vice President Sean Hofherr discusses how GeneDx utilizes the latest advancements in sequencing technology to identify genetic findings that may be linked with rare diseases.

Let’s begin with a few words about who you are and what you do.

I am a trained clinical molecular and clinical biochemical geneticist. I have been at GeneDx for four years now. I first came into the company as the Chief Scientific Officer, and a year later I took over the lab director role, where I oversee all the regulatory and licensing aspects of the company. More recently, I moved into the executive vice president role and it just broadened the scope of the areas that I cover. 

Before I came to GeneDx, I worked at the Children’s National Medical Center in Washington D.C., where I built and ran a molecular laboratory, pretty much from scratch. I created a robust molecular genetic testing program and oversaw the biochemical genetics laboratory. Before that, I trained at Mayo Clinic and got my Ph.D. at Baylor College of Medicine in Houston.

Please describe the story behind the company’s start and evolution over the years.

GeneDx began21 years ago, built from the desire of a couple of researchers at the National Institute of Health, Sherri Bale and John Compton, to apply different molecular technologies for diagnosing patients. They were translational researchers involved with patients and providers but Sheri and John weren’t set up to be able to offer genetic testing as a service. They stepped into the unknown and started GeneDx. From the very beginning, GeneDx’s focus has always been around the diagnosis of rare diseases. 

Our GeneDx mascot is a zebra, which has become the symbol of rare disease because of the medical school saying, “When You Hear Hoofbeats, Look for Horses, Not Zebras”. This is typical medical school training: always look for the most obvious explanations first, not the uncommon possibilities. In rare diseases, uncommon is the norm. At GeneDx, our goal has always been to diagnose the zebras and we continue to be at the forefront of genetic testing services for rare diseases. 

As technology has come to market, it allows us to do things that we previously weren’t able to do. GeneDx consistently leads the pack in providing diagnostic services utilizing new technologies. We quickly master new laboratory methods to solve additional genetic problems. 

What kind of tests does your company offer? How do they improve doctors’ decision-making?

We are most recognized for our whole exome and whole genome sequencing which are hugely valuable tools in the clinic. Over the 10 years that exome sequencing has been available, we have tested hundreds of thousands of individuals. While there are several companies including ours that offer genetic testing, I would say we are doing significantly more exome sequencing in the U.S. than anybody else. More recently, we started to deploy genome sequencing, which has changed the paradigm for genetic testing. 

When GeneDx was founded, the general expectation was that one disorder would link with one gene. For instance, if somebody had symptoms of cystic fibrosis, you would test for the CFTR gene, look for genetic alterations in that gene, and would determine the molecular diagnosis. 

As massively parallel next-generation sequencing (NGS) became available, we were able to simultaneously test multiple targets in any given patient. That was the first shift that transitioned genetic testing. 

When a healthcare provider sees a patient, they are no longer looking for a single gene that could be causing the patient’s symptoms; they are looking for a set of genes. This change happened around 12 years ago with the launch of next-generation sequencing panels.  At first, the panels were small, consisting of 5, 10, or 15 genes tied to a patient’s specific condition. However, the process still depended on iterative testing where the provider had to know exactly what they were looking for. Sometimes, they would start with a single gene test and then reflex to a multi-gene panel. Sometimes they would order several individual gene tests and then reflex to a multi-gene panel. 

More recently, exome sequencing and genome sequencing have allowed us to look for anything that could potentially match a patient’s phenotype. Rather than coming with a very specific set of genes to look at, we are now looking at every single gene. In exome, it’s all about the coding portions of the genome. We analyze and interpret the results based on the patient’s clinical presentation. Providers are no longer obligated to stay at the forefront of genetic discovery and know every single gene and every single mutation that could be seen in a patient. 

We’re at the point today where rapid genome sequencing, especially in the neonatal intensive care unit (NICU), is becoming an extremely useful tool. There have been promising results from pediatric hospitals that have been pioneering this effort, as well as from companies like ours that offer rapid genome tests with a one-week turnaround time. This is starting to change the way that providers are practicing medicine, in NICUs and beyond. It’s been amazing and I think GeneDx’s role in that process has been instrumental.  

Here’s a view of GeneDx’s test catalog:

Interview with GeneDx

What do you do with the big data that you collect, and what are you hoping to achieve from it?

For the most part, we use the data to enrich our knowledge base, and, because we test so many patients, the data makes it easier for us to answer questions for the next patient in a much more informative way. 

For example, if we find a genetic variant we think could potentially be significant in a single patient, we might not be sure, because the gene may be one in which nobody has ever reported any mutations or the variant might be one with uncertain significance. A year later, we might have two more patients with similar symptoms, who also happen to have that same genetic variant. By comparing against previous cases, we can gradually confirm whether the finding is significant. 

If we determine the variant is the cause of the patients’ symptoms, we may now classify the finding as pathogenic. Whenever we have new findings, we contact the healthcare providers from the previous patients and offer to reanalyze their patients’ results. If they agree, we issue a new report that says whether the patient had the same pathogenic finding, whereas before it may have been something we weren’t sure about. This way, all patients benefit from our expanded knowledgebase. 

The other way we use data is by working with different clinical groups in a research capacity. We just had a recent publication in JAMA about the genetic etiology of cerebral palsy (CP). We were looking at a large cohort of patients with Geisinger Health System in Pennsylvania, and we found that about 30% of children and about 10% of adults with cerebral palsy have genetic mutations that are the cause of their condition. 

We’re also involved in public databases. We have a very open model for sharing de-identified data so, while we use it to enrich our work, we also use it to enrich the entire medical field. We contribute to websites like ClinVar, ClinGen, GeneMatcher, and other databases that help broaden the knowledge base for the field of genetics and the overall rare disease community.

With such outstanding benefits, why aren’t genetic tests a  standard part of our healthcare systems?

Genetic testing has become more integrated into our healthcare systems, but there’s still a huge gap between what we all envisioned with the human genome sequencing project and the current state of genetics in healthcare.  

One of the biggest reasons is the lack of training in medical schools. Quite a few studies have shown that MDs are only getting a minimal amount of genetics training in medical school. That’s probably the biggest challenge because you need to have all providers familiar enough with genetics to know when they should be engaging in genetic testing. Another reason is that genetics and genetic training is still fairly complicated. 

Clinical Geneticists typically train for several years on top of their Pediatrics residency, but they actually make less money than if they just finished with a pediatric specialty. That de-incentivizes doctors from learning and practicing genetics as their primary focus. As a result, the number of clinical geneticists in the field is quite limited.

Likewise, genetic testing continues to be fairly expensive. Thankfully, we’ve had amazing improvements in technology that allowed the price to come down significantly. 

Insurance companies, who are the payers for most genetic testing in the U.S., are getting more and more creative in pushing back on paying for genetic tests. As a result, the burden of coverage is extremely high, as you have to prove that the genetic test will dramatically change the immediate care of the patient. 

A genetic diagnosis may qualify patients for social services, social care, or access to patient advocacy groups. Diagnosed patients may be given a different therapy regimen, but generally, there’s no treatment for each individual genetic disease. Therefore, the benefit to the insurance company is softer from a financial standpoint and that too has been a challenge, especially recently.

We’re finally at the point, from a scale and knowledge perspective, to start deploying genomics in a clinical setting for routine care. As time goes on, we’ll see more genetic testing being incorporated into our healthcare system. Being one of the major genetic testing service providers in the U.S., we hope to be at the forefront of this advancement.

How has GeneDx contributed to the fight against COVID-19?

Our parent company, BioReference Laboratories, was one of the first laboratories to launch COVID testing outside of New York City, the epicenter of COVID in the U.S. There was a massive increase in New York City cases and so BioReference partnered with the New York municipality to provide COVID testing. 

About six weeks later, we leveraged our expertise and technology to also bring up COVID testing so we could support BioReference Laboratories in their efforts. We launched COVID testing on April 20th, 2020 and we’ve continued to run COVID testing since that point. Our capacity continues to increase, all under the BioReference banner. 

Which trends or technologies do you find to be particularly exciting these days?

We’re always keeping a close eye on any kind of sequencing technology, and we’ve seen some impressive advancements. Short-read sequencing continues to be the leader. However, long-read technology has come a long way and is quite powerful as well. Currently, we think of it as a supplement to short-read sequencing, but I believe it will reveal its own potential in the long run. 

In some cases, it might seem as though the parents of a child born with a genetic condition don’t have the condition themselves. However, when we test samples from both the child and the parents, we can actually find low-level mosaicism in the parents. The only way to detect this low-level mosaicism is by using quantitative technology like a digital droplet. 

Optical mapping has also been pretty fascinating, both in-silico optical mappings like 10X Genomics or even physical optical mapping like Bionano. These are all technologies that we’re keeping a close eye on.

How do you envision the future of your industry?

We’re not too far away from the point where we could all have our genomes sequenced as part of standard, preventative healthcare. As new disease-causing genes are discovered, we will be able to incorporate the findings with already existing genetic sequencing data to enable access to continuously up-to-date genetic results throughout our lives. 

The next step would be to link up all individual health information into a single place to provide a complete health record for each of us. For example, if a person experiences a change in blood pressure, the new information could be added to their health record along with their genome results and other health information such as last year’s EKG findings. Having your own portable health record would allow you to access the information anytime. The communication would need to go both ways so that when we, the genetic testing laboratory, have new findings to share, we are able to communicate dynamically with providers and patients. 

Historically, genetic testing has been entirely provider-driven. Providers order our tests, and they are the ones who receive the reports, which are not suited for a layperson. Many providers struggle to read and understand the reports, and we are trying to change that. Figuring out how to make the reports easy to understand is probably the biggest challenge in this field because the results are so different from traditional laboratory medicine. There’s a lot of power in genomics and we’re only scraping the surface. Eventually, I expect that genetic testing will make its way into all aspects of medicine. 

About Author
Ditsa Keren
Ditsa Keren

Ditsa Keren is a technology blogger and entrepreneur with a strong passion for biology, ecology and the environment. In recent years, Ditsa has been specializing in technical and scientific writing, covering topics like biotechnology, algae cultivation, nutrition, and women's health.

Ditsa Keren is a technology blogger and entrepreneur with a strong passion for biology, ecology and the environment. In recent years, Ditsa has been specializing in technical and scientific writing, covering topics like biotechnology, algae cultivation, nutrition, and women's health.