Scientists have discovered that a common cause of sudden heart death has been misunderstood because researchers didn't appropriately account for racial differences in their studies.
The findings, published online Wednesday in the New England Journal of Medicine, have implications far beyond this particular inherited disease, called hypertrophic cardiomyopathy, or HCM. Researchers say the results also sound a cautionary note for many other illnesses that have been identified through genetic markers.
HCM gained attention in the 1980s after several seemingly healthy athletes, including the rising basketball talent, Hank Gathers, suddenly died from it. Scientists had figured out that the propensity for developing HCM is passed along as a genetic trait; the condition affects about one in 500 Americans.
Tarika Mingo, a psychiatric social worker in New York City, first realized something was wrong with her own heart several years ago, when she became so short of breath during gentle activity that she nearly passed out. In 2014 her doctors accurately diagnosed her with HCM. They performed open-heart surgery and reduced her risk of sudden death. She still feels the effect of the disease, however.
"I have to see the cardiologist every three to six months," she tells Shots. "I have to take my medicine every day. The heat is not my best friend, so it limits my social activities. We just had a heat wave and I was stuck in the house."
The diagnosis also sent reverberations through her family. That's because the likelihood of developing HCM follows a simple, inherited pattern: If your parent has the disease, your likelihood of developing it is 50:50. So she urged her entire family to get checked out. Mingo's 16-year-old son shows no signs of having inherited the condition, but her 29-year-old sister has some ominous symptoms.
As part of the diagnosis, doctors turn to genetic testing. But, while the inheritance of this disease follows a simple pattern, the genes that control it reveal a much more complicated story than geneticists realized until very recently.
And that applies to many other genetic traits that are now commonly diagnosed in medical labs.
In HCM, it turns out, any one of about a dozen genes can be damaged in ways that lead to the illness, and there are many different possible mutations in each of these genes. So there are many ways the disease can be passed down.
What's more, some of the variants that researchers originally flagged as disease-causing mutations have actually turned out to be benign.
Dr. Isaac Kohane at Harvard Medical School says a postdoctoral fellow working with him, Arjun Manrai, came across this serious problem of misdiagnosis quite by accident.
They were studying the genetic variants related to HCM. While the disease is observed to occur in about one in 500 people, "we saw that the variants that were ostensibly causing disease seemed to add up to much more than one in 500," he says.
In fact, the supposedly risky gene variants appeared in one out of 10 or one out of 20 people of African descent — an impossibly high number.
"Something must be wrong," Kohane realized. "Something must have been awry."
Kohane and his colleagues think they now may have solved that mystery.
When scientists originally went looking for these genes, Kohane explains, they compared the genetics of families affected by the illness with a sample of healthy people.
But here's the catch: People in the healthy comparison groups in these studies were white; whereas some people in the studies with HCM apparently had some African ancestry. As a result, some of the gene variants flagged as being linked to the illness simply represented racial differences between the groups and had nothing to do with HCM.
That problem would likely have been avoided if the original scientists had added four or five African-Americans to the control group, Kohane says.
It turns out that two of these variants commonly identified in African-Americans actually don't pose a health risk at all. That means many people may have been inadvertently misled about their risk of developing this disease.
"I've had to evaluate a large number of athletes with borderline anatomical findings," suggesting they had the heart condition, said Dr. Barry Maron, a leading expert on hypertrophic cardiomyopathy at Tufts Medical Center. He has also served as a consultant for top college athletic departments.
"Could some be false positives, and [mistakenly] disqualified from sports?" Maron asks. "I don't know for sure, but it's possible."
Promising athletic careers may have come to an abrupt halt, based on the results of genetic tests that turned out to be misleading. On the other hand, Tarika Mingo worries that insurance companies and doctors won't be as committed to diagnosis and treatment of HCM patients if there is no clear genetic marker. So she's nervous about seeing any genetic marker reclassified as benign.
Meanwhile, it's not clear whether these misidentified traits are still being linked with the disease, Kohane says. Genetic testing labs work independently, so the test for HCM can vary from one company to the next.
"The leading laboratories that do genetic testing make sure that they update their findings as these results come in," he says. But other labs may just adopt a panel of tests and stick with it.
Maron and Kohane say this discovery has implications that go far beyond sudden cardiac death. It underscores the point that even diseases that appear to have simple genetics are in fact usually quite complicated.
"Is HCM one of these diseases you either have or you don't?" Kohane asks. "Or is it like almost everything else we're coming to learn about, where it's a matter of degree."
Genetic testing, he says, has lulled us all into thinking that diseases can be boiled down to yes or no questions. But, increasingly, that does not seem to be the case.
"It just turns out that the genome is as complicated and as unique as each one of us," Kohane says.
DAVID GREENE, HOST:
We're going to hear about genetic testing. It is done at medical labs to help people identify risks to their health. But genetic tests are not always as reliable as you would hope. Just take heart disease genes. Some of these genes have been misidentified because researchers did not get the right racial balance in their testing. Here's NPR's Richard Harris.
RICHARD HARRIS, BYLINE: A heart condition called hypertrophic cardiomyopathy is a leading cause of sudden heart death. Dr. Isaac Kohane at the Harvard Medical School says it follows a classic genetic pattern, which should make it easy to track through gene testing.
ISAAC KOHANE: You don't need two copies of the mutated gene. Just one copy, and you have the disease, so it's a textbook case.
HARRIS: In New York City, Tarika Mingo knows all too well the consequences of inheriting this trait. Shortness of breath and other worsening symptoms sent her to the doctors two years ago, and they diagnosed the disease in her.
TARIKA MINGO: So ten months ago, I had open-heart surgery. I had what's called a septal myectomy and a mitral valve repair.
HARRIS: Still, she lives with the ongoing consequences of this disease, including frequent doctor trips and daily medications.
MINGO: The heat is not my best friend, so it limits my social activities. We just had a heat wave, and I was stuck in the house.
HARRIS: Testing revealed a genetic variant in her, which is apparently the risk factor that runs through her family. Each member of her immediate family has a 50/50 chance of carrying the variant. Her 29-year-old sister has been having heart problems.
MINGO: And I've encouraged my siblings to get tested genetically.
HARRIS: But the genetic testing for this disease isn't as reliable as you would expect any. One of about a dozen genes can be involved in the disease, and each has many different variants. Dr. Kohane's lab at Harvard was cataloguing those. They expected to find the dangerous trait in 1 in 500 people, since that's how often the disease appears.
KOHANE: We saw that the variants that were ostensibly causing the disease seemed to add up to much more than 1 in 500.
HARRIS: This was specifically the case in people with African ancestry.
KOHANE: Something must be wrong.
HARRIS: Kohane and his colleagues have now explained that problem in the New England Journal of Medicine. It seems that researchers who originally identified some of those variants didn't take enough care to include healthy people of African descent in their studies. As a result, some of the gene variants in African-Americans are, in fact, false alarms and not linked to the disease. One consequence could well affect college athletes. Dr. Barry Maron at the Tufts Medical Center consults for many schools who come to him when they have uncertain results from physical cardiac tests. They may then run genetic tests.
BARRY MARON: In that situation, a false-positive test could give a false diagnosis to an athlete who doesn't have hypertrophic cardiomyopathy. And this could lead to disqualification from competitive, intense sports.
HARRIS: And the results extend far beyond athletes, to families like Tarika Mingo's.
MARON: False positives are difficult because they're indelible.
HARRIS: The fear can never be erased. And Tarika Mingo says if doctors told her the trait identified in her family was actually benign, she wouldn't put much trust in that. Doctors Maron and Kohane draw a larger lesson from all this. Even a disease like this with seemingly simple genetics turns out to be pretty complicated.
KOHANE: It just turns out that the genome is as complicated and unique as each one of us.
HARRIS: So people who are expecting tidy yes-or-no answers from any genetic test need to dial back their expectations. Richard Harris, NPR News. Transcript provided by NPR, Copyright NPR.