Genetic testing beneficial in critically ill adults

Genomic testing—sequencing an individual’s entire genome or all of their genes—has become affordable and accessible enough to serve as a key diagnostic tool. In fact, its use in infants and children with suspected genetic disease or with complex medical histories has been shown to lead to wide-ranging health-care cost savings and improved outcomes.

Despite well-documented benefits in the pediatric population, genomic testing is not commonly used in adults, largely because it is believed that the likelihood of finding undiagnosed genetic conditions decreases with age.

Now, a team of researchers led by Theodore G. Drivas of the Perelman School of Medicine has challenged this idea, finding previously unknown genetic diagnoses in a large percent of adults admitted to intensive care units (ICUs) at Penn. The findings are published in The American Journal of Human Genetics.

“Our study shows that genetic disorders are a surprisingly common reason people end up in the intensive care unit—even in adults,” says Drivas. “Genetic disease does not only affect pediatric patients and young adults but appears to be important—and underdiagnosed—across the life span.”

The researchers retrospectively analyzed whole exome sequencing (WES) data—which captures the protein-coding regions of DNA known as exons—from 365 adults aged 18 to 40 years who had been admitted to an ICU in the University of Pennsylvania Health System. Two physicians board certified in both medical genetics and internal medicine reviewed each WES report and patient chart.

According to Drivas, they found that nearly one in four patients in this study had a genetic condition related to their ICU admission, which was unknown to nearly half of those patients and their doctors. Additionally, for over 75% of these patients, these diagnoses call for specific management guidelines.

“Importantly, we found no correlation between patient age and the likelihood of having a genetic diagnosis,” says Drivas. “This means that older adults were just as likely as younger adults to have a genetic diagnosis causing their critical illness, which is contrary to what many assumed would be true.”

The study also found “striking” race-based disparities in access to genetic testing. “Black patients are significantly less likely to have known/documented diagnoses,” write the authors, noting that while diagnoses were documented for 63.1% of white patients and 100% of Asian patients, they were only documented for 27.7% of Black patients.

“This disparity cannot be explained by demographic differences or differences in overall diagnostic rate of exome sequencing between these different groups,” write the authors. “It is likely that these disparities reflect biases in physician referral practices for patients of different backgrounds and societal barriers, including long wait times and limited hours for genetics clinic evaluation.”

Drivas notes, “In addition to diagnosing genetic diseases, when we also consider the added benefit of exome/genome sequencing in providing care teams with valuable pharmacogenomic information that can help direct medication dosing to ensure efficacy and prevent adverse events, our data suggest that the majority of critically ill patients could benefit from such testing. However, such testing is only very rarely performed in critically ill adults.”

But Drivas and his colleagues have a solution. They recommend offering genetic testing to all adults admitted to the ICU.

“Genetic testing costs little compared to an ICU stay, yet it’s rarely offered to adults,” says Drivas. “Our findings strongly suggest that we should consider offering broad genetic testing to patients as part of their ICU admission; knowing a patient’s genetic diagnosis can mean better care, better survival, and fewer health disparities.”

Currently, Drivas and his team are collaborating with the MyPennGenome project, led by Bogdan Pasaniuc of Penn Medicine, to help with this goal.

“We are hoping to prospectively sequence the genomes of ICU-admitted Penn patients and return these results to the patients and their treatment teams as part of a pilot study,” adds Drivas. “Our hope is that as the utility of broad genetic testing in the critically ill adult patient population continues to be proven through studies like these, the health system will adopt it as part of routine patient care.”

“We have the tools and the data,” he says. “Now we need to make genetic testing standard practice.”

Theodore G. Drivas is an assistant professor of medicine (translational medicine and human genetics in the Department of Medicine and assistant director of scientific outreach of the Penn Medicine BioBank at the Perelman School of Medicine. He is also a co-director of the HHT Center of Excellence at the Hospital of the University of Pennsylvania.

Other authors are Colleen M. Kripke, the Regeneron Genetics Center, and the Penn Medicine BioBank of the Perelman School of Medicine at the University of Pennsylvania and Jessica I. Gold of Northwell Health.

The Penn Medicine BioBank is supported by the Perelman School of Medicine at University of Pennsylvania, a gift from the Smilow family, and the National Center for Advancing Translational Sciences of the National Institutes of Health (NIH) under CTSA award number UL1TR001878. T.G.D. is supported in part by NIH K08 1K08DK127247 and the Burroughs Wellcome Fund. This study itself did not receive external funding.