It started as a mystery with monumental consequences.
Children were dying. Parents were grieving. Doctors were scratching their heads.
University of Iowa pediatric cardiologist Ian Law entered the picture in 2013 after a family that had been living in Wisconsin moved to Iowa with a lot of unanswered questions.
Law, who specializes in treating kids with heart arrhythmias, had discussed the case with colleagues. The family had eight children — six boys and two girls — with a history of passing out while playing sports.
In 2011, one of the boys collapsed while playing baseball. He was 11.
“He stopped running, grabbed his chest, and fell to the ground,” Law said. “He was unresponsive and could not be resuscitated.”
When another of the sons survived a similar episode — also while playing baseball — physicians tested for all the common diseases.
“And nothing came up,” Law said. “But one thing about genetics for sudden cardiac arrests is that it’s evolving rapidly.”
A negative test 10 years ago might not be negative today, he said. Especially with investigators on the case like Law — who along with colleagues here and across the country took on a variety of roles in their care for the family, including sleuth, geneticist, genealogist, marital counselor and lifesaver.
“There is no disease worse than one that takes a child from his parents,” Law said.
The team’s incessant research — poring over family trees and pulling extended family blood samples — would uncover a not-yet-known genetic disorder.
ARTICLE CONTINUES BELOW ADVERTISEMENT
“There is no name yet,” Law told The Gazette. “Our team discovered it.”
‘There must be something going on here’
But the prospect of unearthing a novel genetic anomaly enabling physicians to perform lifesaving interventions seemed remote when the Mennonite family new to Iowa arrived at UI Hospitals and Clinics seven years ago.
“We didn’t really have a great tool to evaluate the patients,” Law said, referencing the initial unremarkable genetic tests. “So we followed them clinically and waited to see if they had an event.”
The 2014 cardiac arrest of another of the family’s sons proved such an event, and upped the research team’s urgency. For starters, they implanted a defibrillator in the 10-year-old.
“That’s when we started collecting blood samples of multiple family members,” Law said.
Because Mennonite families typically have extensive histories, he said, the researchers were able to generate a broad pedigree that allowed them to identify other at-risk families. One relevant family in the 1950s and 1960s had five of seven children die. Another had four of eight children affected, and yet another lost six of eight children before age 12.
Researchers realized, according to Law, “There must be something going on here.”
Culprit found: RYR2 gene mutation
Using a Mayo Clinic laboratory, the team — including Mayo’s Michael Ackerman and David Tester, lead scientist on the case — ran the blood samples, which took time and patience.
“I’d say, ‘Where do we stand with the family? Do we have any clues?’ ” Law said. “And over time, as our investigative techniques became better, we were able to identify the gene mutation.”
They found the implicated mutation in the RYR2 gene. And of the 23 youths whom the research team identified with the inherited mutation, 18 had died sudden deaths.
Law said affected families included a mother and a father with the same genetic mutation — leaving their children with a one in four chance of getting the fatal blend of both bad genes, “one from the mom and one from the dad.”
“When that happens, it creates a very lethal arrhythmia,” Law said. “Whereas if they only get one bad copy from the mom, but a good copy from the dad, they’d be fine.”
Team takes action to save lives
With that new knowledge in hand, the scientists began their interventions — testing the kids and implanting defibrillators where necessary. They also prescribed medication.
“Now that we know that these children are at risk, let’s make sure the child is safe,” Law said.
The proactive measures have been vital. One of the affected children with the genetic condition and an implanted defibrillator at age 27 suffered a cardiac arrest while jumping on a trampoline.
It saved her life.
The researchers also have counseled the kids on who they might choose as a spouse one day.
“If they marry another person in the Mennonite community that has one bad copy, there’s a one in four chance their children will have a life-threatening disease,” he said. “So as much as anyone can do this, we encourage them not to marry someone that has that gene mutation.
“We can offer that to them.”
Although the family Law spent most of his time with lives in rural Iowa, several hours from Des Moines, some of those affected live in Missouri, Wisconsin, Delaware and Pennsylvania.
And Law every six months continues to see the local family, whom he described as smiling, polite, “solid kids.”
“I don’t get the sense that it fazes them,” he said, “Like they’ll say, ‘Well I was out deer hunting, and I was getting ready to shoot and I felt funny, and when I woke up the deer was gone.’ ”
They’ll go on to boast, Law said, “I got a deer an hour later.”
ARTICLE CONTINUES BELOW ADVERTISEMENT
“So they had an arrest, their device probably shocked them, and then they go on with their life,” Law said.
Mother has ‘mixed feelings’ about research
In a CNN report on the discovery recently published in JAMA Cardiology, Tester boasted of the findings’ broader implications.
“Having this genetic biomarker, we can now very easily test any individual for the presence of the mutation,” he told CNN. “Having that ability can potentially save lives.”
Although the local family that worked closely with Law didn’t want to be identified for this story — out of concerns for their privacy — the mother answered questions from The Gazette, via Law, and said her family has navigated their medical journey with both faith and fear.
“Having a child die, and then seeing more of your children pass out and doing CPR is no easy thing,” she said, going on to quote the Bible. “The eternal God is our refuge and underneath are his everlasting arms.”
Although the mother described her reaction to her children’s repeat cardiac episodes as “shocking,” she also remembers learning when she was young that distant family members had lost children suddenly and unexpectedly.
In processing her family’s newly known reality, the woman expressed “mixed feelings” — hinting that she feels responsible in some way — but also relief to have a test allowing early intervention.
“Glad to know we can do a blood test to find out if the children and grandchildren will be affected and yet hating that we are the cause of this heart problem.
“I still have a hard time fully believing we can totally rely on these tests,” she wrote, ending her written comments with a smiley face.
Comments: (319) 339-3158; firstname.lastname@example.org