Understanding the Impacts of Newborn Whole Genome Sequencing

What Is GUARDIAN?

“Guardian is a newborn screening research project. It's not a commercial offering or the standard of care yet. It's a research project in New York City at Columbia University and its associated hospital, New York Presbyterian,” said Kruszka. “The study looks at the utility of newborn screening using a technology called whole genome sequencing, where you're sequencing all 3 billion pieces of information over our genetic code.”

He emphasized that this is a relatively new type of newborn screening, and while other similar projects are going on globally, this one’s focus is specifically on newborns. The study is expected to run for up to four years until 100,000 samples are collected.

Why Whole Genome Sequencing?

The currently available technologies for screening genetic diseases in newborns are limited. “The driving force of newborn screening using whole genome technology is that providers need a technology platform to capture more diseases,” explained Kruszka.

“The current technology is from the 1990s, and that's tandem mass spectrometry. There are only so many diseases providers can screen for using tandem mass. Those conditions are all within a single category called inborn errors of metabolism,” he added.

Whole Genome Sequencing

The whole genome sequencing process is intricate and complex, as collecting samples, running tests, and extrapolating data is a multi-step process.

Collecting Sample

The first step of the procedure requires collecting a blood sample from the patient to be sequenced.

“The team and I are taking the DNA from blood spots. This test goes back 60 years to when Robert Guthrie developed the phenylketonuria (PKU) test, the first newborn screening test. Healthcare professionals prick the baby's heel and put some blood on this little circle called a dry blood spot, explained Kruszka.

“Whole genome sequencing uses the exact same method. Using the cards that New York State Health Department is doing their regular newborn screening on, providers are extracting DNA from newborns using the blood on the blood spot and doing whole genome sequencing through GeneDx at the Gaithersburg lab or GeneDx Sema4.”

The Genome Sequencing Process

After collecting the blood sample, researchers and clinicians can begin dissecting the sample and running a genome sequencing procedure.

“This process is a technology where scientists take these long strands of DNA and chop them up into little pieces, a little over 100 spaces long, and massively parallel sequence all these sequences simultaneously. Instead of doing every base one at a time, this is a fast process. The technology has been around for 15 years, so scientists are sequencing the whole genome. That means sequencing every letter, all three billion base pairs in the human genetic code,” said Kruszka.

GUARDIAN’s Genome Sequencing

After providing LifeScienceIntelligence with an overview of WGS, Kruszka explained how whole genome sequencing is used in the GUARDIAN study.

“The team and I only analyze certain genes for newborn screening purposes. Currently, there are roughly 260 genes that we're looking at, and these were specifically chosen to look at because they meet certain criteria that we've set out for these genes,” revealed Kruszka.

“The research team has only picked 260 genes. We're looking at genes that occur in the first five years of life. So, we're not looking for genes, for example, that would present as adults. A good example would be BRCA1, which is associated with a risk for breast cancer,” he continued.

Beyond looking at genes that appear in early life, the researchers are also focused on genes that have 90% or greater penetrance, meaning that a genetic mutation leads to a 90% chance of actually having the disease.

“The team and I don't want to give false positives to families or initiate unnecessary treatment and increase the anxiety of families if this is not a highly penetrant disease,” justified Kruszka.

Additionally, he explained that there are two categories of genes: category one and category two. Category one genes have a treatment. Approximately 160 of the genes picked for this study are category one genes. Conversely, the 100 genes are category two. These genes do not have a treatment, but the symptoms can be managed with other interventions such as occupational, physical, or speech therapy.

Why Sequence the Whole Genome?

Why sequence the whole genome when only looking at a subset of genes? This may seem like an obvious question.

Kruszka responded, “the advantage of using a whole genome — we call it the whole genome backbone — even though we're looking at 260 genes, is to scale it. So there's no limit on this test, on this technology. We wanted to develop the most comprehensive technology. So let's say there are new cures for some diseases in the next five years. We want to put those genetic diseases onto this backbone because it's very comprehensive.”

GUARDIAN’s Impacts

LifeScienceIntelligence asked Kruszka to discuss GUARDIAN's benefits and potential outcomes on patients, providers, and scientific research.

Ending the Diagnostic Odyssey

Kruszka described the emotional and physical outcomes of patients and their families. For both treatable and untreatable diseases, genetic sequencing means a diagnosis, which, in turn, means that providers can intervene to provide the patient treatment or support.

In addition, diagnosis removes a tremendous burden on the patients’ families. According to a study published in Genetics in Medicine, the direct cost of a genetic disease diagnosis in the first year of the journey is $2,257 in Canada per patient or $1,626.36 in the United States. 

“When a family gets a diagnosis, it often ends a long diagnostic journey where they’ve been going to different doctors, getting different testing, traveling to different hospitals, trying to do what's best for their child,” began Kruszka. “Getting a diagnosis ends this diagnostic odyssey.”

Beyond ending a long-winded journey for diagnosis, these families also find a community of people facing the same struggles they are. “These families get together. They organize. The family groups that have children affected start raising money. They start looking for cures. They start looking at academics. They start trying to save, and in many situations, they start trying to save the child’s life,” he asserted.

Provider Benefits

Having an additional diagnostic tool can help alleviate the anxiety that many doctors experience. According to the Journal of Affective Disorders, during the COVID-19 pandemic, as many as 25.8% of surveyed clinicians had anxiety.

“As providers, we have anxiety when we don't have a diagnosis. We went into medical school, medicine, and nursing school to give people answers, right? It gives us anxiety when we don't,” revealed Kruszka. The ability to give a definitive diagnosis, refer patients, and begin interventional or maintenance treatments is an unmatched asset to those providers struggling to help their patients.

Beyond alleviating provider anxiety, Kruszka believes that this will be a critical resource for medical education. “The general physician medical provider community doesn’t know enough about genetics,” he stated. “This will be a fantastic vehicle to get genetics out there because sometimes people only do something when they have to. When clinicians start genetic screening on infants, people will have to learn this.”

Looking Ahead

As this study progresses and more samples are collected, additional clinical implications will become apparent. According to Kruszka, only about 250 of 100,000 specimens have been collected so far, meaning there’s still a long way to go.

While newborn whole genome sequencing is not yet universal, he hopes that the results of this study and the anticipated benefits, once proven, will incentivize clinicians and healthcare experts to make this a standard of care.

“I would have never imagined in my wildest dreams that geneticists would do this when I was a medical student 25 years ago. I want to emphasize that we're in an amazing time with rare diseases. I would be bold enough to say that genetics is entering a new era. This is the most exciting time for our field,” concluded Kruszka.