Each year, thousands of seemingly healthy young people die suddenly, and in many cases, doctors don't know why.
Scientists in San Diego are starting to solve some of these medical mysteries through genetic sequencing, and their discoveries can have a profound ripple effect on surviving family members.
One of them is Dardie Robinson. She works as a paralegal in Portland, Oregon. Often juggling many legal cases at once, she's the type of person who keeps organized files. But one of the files she's kept in her office over the past year has nothing to do with her work.
"This is my Daniel investigation file," she said, pulling out a thick folder. The case in this file dates back to a call she got on Sept. 23, 2014. It was about her son, Daniel.
"I got a call out of the blue from his girlfriend," Robinson said, tearing up.
"She said the paramedics were there, working on Daniel. That she had found him and he was blue and unresponsive. And I told her, 'Tell him his mama loves him.' And she said, 'I'm sure he can't hear you.' And I said, 'Tell him anyway.' "
She texted her family, telling them to pray for Daniel, then left the office and got in her car.
"And on the way home, I got the call that there was nothing they could do. And he was gone."
Not knowing was the worst part
Daniel was 29 years old and otherwise healthy. Dardie said he was sweet, artistic and had a knack for cooking.
The only indication anything was wrong came two weeks earlier, when Daniel went to the emergency room complaining of shortness of breath. He was told it was probably just anxiety.
At first no one could tell Dardie why her son had suddenly died, but suspicions were swirling by the time of his memorial service.
"That was, to me, really the worst part," she said. "They thought he must have committed suicide. He must’ve taken something. I just kept saying, 'That doesn’t make sense.' "
It wasn't until a month after his death that Dardie started getting some answers. An autopsy revealed no evidence of trauma. She keeps the report in her file so she can go back and re-read its conclusion:
"It is my opinion, based on the circumstances surrounding death and the findings at autopsy, that Mr. Daniel Henry Wiggins died as a result of coronary artery atherosclerosis. The manner of death is natural."
The autopsy gave Dardie some peace of mind. At least now she knew her son had not killed himself. But it also left her unsettled. If this heart problem could kill Daniel at 29, could it strike her five other biological children?
"That was the question," she said. "Is it going to happen again? Which one of my kids? Me? I’m OK if it's me. I’m not OK if it's my kids."
Going beyond the standard autopsy
Not long after she got the autopsy back, Dardie came across a story in the Los Angeles Times about a new study happening in San Diego. Researchers at the Scripps Translational Science Institute were using genetic sequencing to take another look at cases like her son’s.
The researchers wanted to go beyond standard autopsies for cases of sudden unexplained death in people younger than 45. They wanted to perform what they call "molecular autopsies." Dardie saw her chance to get to the bottom of what killed her son.
At first, Scripps planned to focus on local cases from the San Diego County Medical Examiner's Office. Dardie lived in Portland, and Daniel was living in Alabama when he died, so her son's case initially wasn't a perfect fit for the study.
That was the question. Is it going to happen again? Which one of my kids? Me? I'm OK if it's me. I’m not OK if it's my kids.
But Dardie was persistent. She was actually born in San Diego when her father was stationed there in the Navy. She continued emailing the researchers about her son's case.
"Just because I don't live in San Diego now doesn’t mean my heart isn't there," she told them. "And now my son's heart literally is."
Dardie had made a point of preserving Daniel's heart tissue, and when Scripps agreed to look at his case, she had tissue samples shipped to San Diego. She also sent a collection of medical records that could be useful in tracking down a genetic cause of death.
Scripps scientist Ali Torkamani said one of the reasons they agreed to take on Daniel's case was a strong family history of early heart failure.
“The fact that there was more than one sudden death in the family at a young age highlighted the point for us: this is likely a genetic issue,” he said.
A history of sudden death
Daniel, at 29, was by far the youngest. But a number of Dardie’s relatives also had died from sudden heart failure in their 40s and 50s. Her father, who kept his blood pressure down and stayed active refereeing baseball games, had his first major heart attack at 52.
Dardie was always told her family's heart issues were likely due to diet and physical activity. She made sure to eat right and exercise, but in her 40s, she also began preparing for her own sudden death.
She's made sure a co-worker knows where she keeps another file in her office. It contains her will and personal information that might be needed upon her death.
"I had been expecting to die for many years," she said. "The majority of us, we don’t have any warning."
With compelling clues that Daniel’s death may have been related to his DNA, the Scripps researchers sequenced genes from his heart tissue. They also did exome sequencing — looking just at the protein-coding sequences of the genome — on Dardie and Daniel's father.
Torkamani and his colleagues used computational filters to narrow down the number of genes that could have led to sudden death.
"And that’s when we found this mutation in this gene TRPM4," Torkamani said.
Until now, this specific mutation had never been identified in the scientific literature. But the researchers could see it was a severe error, what's known as a "loss-of-function" mutation.
Torkamani said other mutations on the TRPM4 gene have been linked with a disorder called progressive familial heart block. It short-circuits the heart’s electrical signals, eventually causing the heart to simply stop beating.
Scripps researcher Ali Torkamani indicates a mutation on Daniel's TRPM4 gene.
Credit Roland Lizarondo
"It's that mutation that we believe is the cause of sudden death in Daniel and in other family members,” Torkamani said.
The same TRPM4 mutation was found in Dardie. She was the one who passed it down to Daniel.
It's a rare mutation, found in 0.16 percent of the population. But since it's found on an autosomal dominant gene, only one copy is needed to cause the disorder. There's a 50 percent chance Dardie passed it down to her other children, too.
Scripps director Eric Topol oversees the molecular autopsy study. He invited Dardie to speak about her experience at the Future of Genomic Medicine conference put on by Scripps.
Not every case Scripps looks at is this clear-cut, Topol said. Some have returned ambiguous results, or no genetic findings at all.
But he thinks Daniel's case illustrates how a genetic discovery in cases of sudden unexplained death can provide valuable, even life-saving information to surviving family members.
It's that mutation that we believe is the cause of sudden death in Daniel and in other family members.
"Because this is something that is eminently preventable with things like a defibrillator," Topol said. "So whereas all these relatives through many generations had sudden death, we may be able to actually pre-empt this in the future. And that's exciting."
A mission to get family members tested
Dardie is now considering getting a surgically implanted device to protect her heart from what happened to her son's.
Researchers still don't know why the mutation would kill Daniel at 29 while leaving his mother unaffected at 60. They can't say exactly how much risk other mutation carriers are at for sudden death. But Dardie said it would be foolish not to take precautions.
She's also now on a mission to get other family members tested for the mutation. She's using Facebook to reach out to long-lost relatives, telling them they need to get tested for this potentially fatal mutation.
"If you have children, I think you need to be tested. I think you owe it to your child," she said. "I wouldn't want any parent to go through losing their child early when it's preventable."
Some of Dardie's surviving children are sending saliva samples to Scripps for testing.
Her youngest biological daughter, Samantha Wiggins, has already mailed in her sample. "You watch CSI and it’s so easy. They take a Q-tip and swab your mouth. That's not what happens. You sit in a bathroom stall for five minutes trying to spit enough saliva into a small tube," she said.
Wiggins said if there weren't precautions she could take, she wouldn't want to know whether she carried the mutation. The whole experience has put her on edge.
"You're kind of sitting there wondering when — when is it going to happen? Especially to other family members," she said. "It's brought me a sense of anxiety about everybody else.”
But now that testing could prevent other deaths, Wiggins has been talking with other family members about getting tested.
Daniel did something significant. He gave us answers that'll benefit not just dozens, but potentially, down the road, hundreds of people.
Dardie comes from a big family. She said dozens — even hundreds — could end up getting tested for the mutation. It can be an awkward conversation, and not everyone is immediately on board with getting tested. But she thinks it's important to make sure Daniel didn't die in vain.
"Daniel did something significant. He gave us answers that'll benefit not just dozens, but potentially, down the road, hundreds of people. Maybe even thousands. Because I don't believe that this is just limited to my family," she said.
'Personal utility'
The Scripps researchers say there's always a level of uncertainty involved in linking genes with sudden unexplained deaths.
There's even some uncertainty in this case. They can't go back and test people from previous generations of Dardie's family to determine whether they died because of the mutation or because of more typical age-related heart disease. Torkamani said he's 95 percent sure the mutation killed Daniel, but he leaves some room for doubt.
With those caveats, the researchers still believe certain discoveries they're making will end up preventing similar deaths in the future.
In addition to providing individuals with answers about the sudden deaths in their family, the researchers are working to build a database of genetic markers known to contribute to sudden death. That information could improve genetic screening and help susceptible patients take preventative measures.
But Torkamani said it's not just about "clinical utility" — it's also about "personal utility." He hopes genetic sequencing becomes more common for inconclusive autopsies so that fewer families will have to live with the pain of not knowing why their loved one is gone.