The first time the seemingly healthy woman gave birth, she went into heart failure. She recovered and went on to deliver her second child a few years later. Doctors cleared the woman to go home with her newborn.
But within months, the woman in her early 20s was rushed back to the hospital, again in heart failure, and ultimately died in a Penn Medicine intensive care unit.
Several years later, a new study has solved the mystery behind her decline: an undiagnosed genetic condition.
The woman is one of many adults whose fates could possibly have been changed with a DNA test. The study, published in The American Journal of Human Genetics, found that one in four adult patients in intensive care units across the Penn health system had a genetic condition linked to the medical issue for which they were admitted. Half were unknown at the time.
“I thought it would be a concerning number, but this was larger than even I thought it was going to be,” said Theodore Drivas, a medical geneticist at the Hospital of the University of Pennsylvania and senior author on the study.
The researchers also found that the chances of a genetic condition being caught varied widely by race. Sixty-three percent of white patients knew about their condition, compared to only 22.7% of Black patients.
This was based on a sample of 365 patients ages 18 to 40 admitted to an ICU at Penn who had signed up for the Penn Medicine BioBank, a repository for health-related data used for research. Their blood samples were in the bank, allowing Drivas and his team to retrospectively sequence their genomes for disease-causing mutations.
When they sequenced the woman’s genome, they found she had a mutation in a gene called Titin that’s known to cause an especially high risk of heart failure in women during and after pregnancy.
“We probably would have managed her differently if we knew,” Drivas said.
Doctors could have periodically monitored her heart function after the second pregnancy. Instead, she went home after giving birth and only came back a few months later when her heart failure had progressed.
Similarly, another patient had multiple aneurysms following surgery that could have possibly been prevented if she had been screened for her genetic condition.
Though the vast majority of patients in this study survived their ICU visit, many could have received more targeted care had their condition been found. Three-quarters of the disorders had standard medical management recommendations available.
It’s unknown if the outcomes of the patients studied could have been improved. The study did not identify individual patients, including the woman whose death after childbirth was cited as an example.
The issue is that genetic testing is rarely offered to adults, even when they are critically ill, Drivas said.
He sees this study as a call to action for ICU doctors to implement universal genetic testing — which is now widely available and often costs as little as a few hundred dollars — for all adults, so that no one goes undiagnosed.
“We need to switch to a model where the default is to send [patients for] genetic testing, not the exception,” he said.
Test adults, too
For decades, the medical field has operated under the assumption that the older you are, the less likely you are to have a genetic disorder, Drivas explained.
The reason for that is a lot of genetic diseases show up in early childhood. Doctors tend to look for those so-called “pediatric-onset” disorders, rather than ones that appear later in life.
“We just assume, if you’re 20 years or older, you can’t possibly have a genetic disease,” he said.
Plus, the threshold for getting tested is high. Conditions that cause intellectual impairment or affect multiple parts of the body are more obvious signs of a genetic condition.
Meanwhile, most of the diseases found in Drivas’ study only cause symptoms in adulthood, and may affect just one organ.
That bias is also reflected in the workforce, with most medical geneticists trained to work with children, not adults, Drivas added.
The genetic conditions most commonly found in this study were cystic fibrosis and Marfan syndrome, both of which tended to already be diagnosed.
The diseases that were commonly missed included cardiomyopathies, which affect the heart muscle and increase the risk of heart failure.
Other commonly missed genetic conditions were those that increased the risk of aneurysms, which is an abnormal bulging of an artery caused by weakness in the artery wall, the study found.
A woman in her 30s had shown up to the ICU with multiple aneurysms around her brain and underwent a standard surgery to treat them. But the treatment ended up causing her to develop more aneurysms at the sites where doctors had been accessing her arteries.
This was characteristic of a condition called vascular Ehlers-Danlos syndrome, which is caused by mutations in the COL3A1 gene. However, the woman had never been offered genetic testing.
When Drivas sequenced her genome, he confirmed she indeed had the mutation. Had they known, they could have warned doctors not to perform that particular procedure.
“We would have said, ‘Hey, stop touching her arteries. They’re really fragile,’” he said.
Most of the patients included in this study had their first ICU visit within the past 10 years. The researchers hope to eventually return these testing results to the patients in the study, so that they can get more informed care going forward.
A need for universal testing
Drivas isn’t sure why the racial disparity in diagnoses is so high. It tended to be reflected in conditions that were less obvious or perhaps were not causing symptoms yet.
The solution to these disparities may be to implement universal testing in ICUs.
A study from the University of Washington had shown that Black children were much less likely to get genetic diagnoses than their white counterparts. However, when they made genetic testing the default in the neonatal ICU, “that disparity goes away completely, and everyone gets good care,” he said.
Genetic testing is more feasible today than previous decades, thanks to the costs getting lower and the process getting faster.
For example, if someone presents with heart failure, doctors could order a targeted gene panel that should cost no more than $250 and, for most patients, be covered by insurance, according to Drivas.
“Price has gone down, the reliability of testing has gone way up, and so it just makes it, in my opinion, kind of a no-brainer to get this done,” he said.