• Researchers used whole genome sequencing to bring together monogenic and polygenic testing, two methods that are usually separated in both research and clinical practice.
• Experts say many more physicians should be using genetic testing, although a large portion of the medical workforce is not yet trained to interpret it.
• The results provide an early foundation for creating targeted treatments tailored to each person's unique genetic profile.

New Genetic Approach to Predicting Dangerous Heart Rhythms

In a new study from Northwestern Medicine, researchers have created a more refined genetic risk score that helps determine whether a person is likely to develop arrhythmia, a condition in which the heart beats irregularly. Arrhythmias can lead to serious medical problems, including atrial fibrillation (AFib) and sudden cardiac death.

The team reports that this improved method strengthens the accuracy of heart disease risk prediction while also offering a broad framework for genetic testing. According to the scientists, the same strategy could be adapted to assess other complex, genetically influenced conditions such as cancer, Parkinson's Disease and autism.

Building a More Complete Genetic Picture

"It's a very cool approach in which we are combining rare gene variants with common gene variants and then adding in non-coding genome information. To our knowledge, no one has used this comprehensive approach before, so it's really a roadmap of how to do that," said co-corresponding author Dr. Elizabeth McNally, director of the Center for Genetic Testing and a professor of medicine in the division of cardiology and of biochemistry and molecular genetics at Northwestern University Feinberg School of Medicine.

The researchers say their findings could support the development of targeted treatments shaped around an individual's full genetic profile. They also note that this type of analysis may allow clinicians to identify people at risk long before any symptoms arise.

The study, which analyzed data from 1,119 participants, was published on November 11 in Cell Reports Medicine.

Integrating Three Major Genetic Testing Methods

Current genetic testing typically falls into one of three separate categories:

• Monogenic testing: Identifies rare mutations in a single gene, similar to spotting a typo in a single word.
• Polygenic testing: Looks at many common gene variants to estimate overall risk, similar to examining the tone of a chapter.
• Genome sequencing: Reads the complete genetic code, much like reviewing an entire book.

"Genetic researchers, companies and geneticists often operate in silos," McNally said. "The companies that offer gene panel testing are not the same ones that provide polygenic risk scores."

In this study, the team combined information from all three genetic sources to produce a fuller view of disease risk. This integrated method uncovers rare mutations, evaluates cumulative genetic effects and reveals subtle patterns across the entire genome.

"When you sequence the whole genome, you can say, 'Let me look at this cardiomyopathy gene component, the gene panel and the polygenic component.' By combining the data together, you get a very high odds ratio of identifying who is at highest risk, and that's where we think this approach can really improve upon what is currently used," McNally said.

Why Physicians Need Greater Access to Genetic Testing

Cardiologists usually assess heart risk based on symptoms, family history and diagnostic tools such as EKGs, echocardiograms and MRIs. McNally said she also incorporates genetic testing into her patient evaluations.

"It helps me manage that patient better, know who's at greatest risk, and if we think the risk is really high, we'll recommend defibrillators for patients like that," McNally said. "Knowledge is power."

Despite the benefits, genetic testing remains underused. McNally said that only an estimated 1 to 5% of people who would benefit from genetic testing actually receive it. Even within cancer care, where genetic links are widely recognized, only 10 to 20% of eligible patients undergo testing.

"We need to improve uptake," McNally said. "The biggest challenge is a workforce that isn't trained in how to use genetic testing. As polygenic risk scores become more common, our approach will become even more valuable."

How Researchers Carried Out the Study

The research team enrolled 523 people diagnosed with arrhythmias, some of whom also had heart failure. They thoroughly reviewed each participant's records, including data directly from implanted devices, to confirm the diagnoses. Afterward, the scientists sequenced each person's genome and used both monogenic and polygenic testing to calculate a risk score.

They then compared these results to the genomes of 596 control participants drawn from the NUgene biobank. These control individuals were age 40 or older and had no known history of cardiac disease.

"It was painstaking going through 500-plus records and making sure that the people in the study really belonged in the study," McNally said.

The paper is titled "A combined genomic arrhythmia propensity score delineates cumulative risk." Additional Northwestern contributors include Tanner Monroe, Megan Puckelwartz, Lorenzo Pesce, Dr. Alfred George and Dr. Gregory Webster.

This advance builds on more than ten years of work at the Gene Editing Institute, where scientists have closely investigated NRF2 and its role in therapy resistance. Their findings showed consistent results in both laboratory tests using human lung cancer cell lines and in animal studies designed to mirror real tumor behavior.

"We've seen compelling evidence at every stage of research," said Kelly Banas, Ph.D., lead author of the study and associate director of research at the Gene Editing Institute. "It's a strong foundation for taking the next step toward clinical trials."

Expanding the Impact Beyond One Cancer Type

The study focused on lung squamous cell carcinoma, a fast-growing form of non-small cell lung cancer (NSCLC) that represents 20% to 30% of all lung cancer cases, according to the American Cancer Society. More than 190,000 people in the U.S. are expected to receive a lung cancer diagnosis in 2025.

Although the work concentrated on this specific disease, the findings point to broader applications. NRF2 overactivity plays a major role in chemotherapy resistance in several solid tumors, including cancers of the liver, esophagus and head and neck. These results indicate that CRISPR approaches aimed at NRF2 could eventually help restore drug sensitivity across multiple treatment-resistant cancers.

"This is a significant step toward overcoming one of the biggest challenges in cancer therapy -- drug resistance," Banas said. "By targeting a key transcription factor that drives resistance, we've shown that gene editing can re-sensitize tumors to standard treatment. We're hopeful that in clinical trials and beyond, this is what will allow chemotherapy to improve outcomes for patients and could enable them to remain healthier during the entirety of their treatment regimen."

Pinpointing a Mutation That Shields Tumors

The team focused on a tumor-specific mutation in the NRF2 gene known as R34G. NRF2 serves as a master controller of how cells respond to stress, and when it becomes overly active, cancer cells are better able to survive chemotherapy.

To counter this, researchers used CRISPR/Cas9 to engineer lung cancer cells carrying the R34G mutation and then knocked out the NRF2 gene. This change restored the cells' responsiveness to widely used chemotherapy drugs such as carboplatin and paclitaxel. In animal models, tumors treated directly with CRISPR to remove NRF2 grew more slowly and responded more effectively to chemotherapy.

"This work brings transformational change to how we think about treating resistant cancers," said Eric Kmiec, Ph.D., senior author of the study and executive director of the Gene Editing Institute. "Instead of developing entirely new drugs, we are using gene editing to make existing ones effective again."

Significant Benefits Even With Partial Gene Editing

One of the most notable findings was that editing only 20% to 40% of tumor cells was enough to enhance chemotherapy response and reduce tumor size. This insight is important for clinical treatment, since altering every cancer cell in a tumor may not be possible.

For mouse studies, the researchers delivered CRISPR using lipid nanoparticles (LNPs), a non-viral system that offers efficiency while limiting the risk of unwanted genetic changes. Sequencing showed that the edits were highly targeted to the mutated NRF2 gene, with very few unintended modifications elsewhere in the genome.

"The power of this CRISPR therapy lies in its precision. It's like an arrow that hits only the bullseye," said Banas. "This level of specificity with minimal unanticipated genomic side effects offers real hope for the cancer patients who could one day receive this treatment."