Autopsies offered no clue. The children’s hearts seemed normal. The family had what they called “the curse of sudden death.” And forensic doctors couldn’t understand why.
After the death of the first two children, a forensic doctor who performed the autopsies contacted researchers at the Windland Smith Rice Sudden Death Genomics Laboratory at Mayo Clinic in 2004. The laboratory researchers had pioneered the concept of molecular autopsy, using genetic tests. to understand the cause of death in sudden unexplained cases, and the examiner wanted to see if they could shed light on the mystery that affected the Amish community.
The team suspected that a gene called RYR2 could be the culprit: gene mutations can cause an arrhythmic heart disorder that can cause fainting, seizures or even sudden cardiac death. But when they analyzed the gene to verify mutations, nothing appeared.
The case remained cold for more than a decade. As the years went by, pediatric cardiologists and genetic counselors from other parts of the country contacted the laboratory about other Amish families whose children had also died suddenly, all seeking answers about this heartbreaking phenomenon.
“When we began to build the family structure, it became clear to us that it was probably a recessive disorder,” David Tester, the lead scientist in the case, told CNN. “With more information and more technological advances in terms of being able to observe genes, we were able to put together this puzzle.”
The children probably had a common ancestor
It turns out that it was RYR2, the gene that researchers had suspected all along. But there was not a single error in the gene. More than 300,000 base pairs in the gene had doubled.
“We finally discovered that it was an autosomal recessive condition in which the two bad duplications came from both parents, and those children had the bad luck of receiving the double dose,” Michael Ackerman, director of the Windland Sudden Death Genomics Laboratory, told CNN Smith Rice .
To develop the duplication that causes sudden death, a child has to inherit a mutated gene from each parent, whose chances are 25 percent. That four children in a family inherited the mutation and died sudden deaths is incredibly unfortunate, Ackerman said.
The Amish may be more vulnerable to hereditary recessive conditions because they descend from a small number of ancestors and tend to marry, Tester said. The two families studied in the report are apparently unrelated, but because all children had exactly the same duplication in a gene inherited from both parents, Ackerman said they are likely to have a common ancestor.
The discovery can help prevent sudden death.
Now that researchers know this genetic marker, there are measures that medical professionals can take to prevent sudden deaths in other Amish children, Tester said.
“Having this genetic biomarker, we can now easily evaluate any individual for the presence of the mutation,” he said. “Having that ability can potentially save lives.”
Knowing who has the mutation and who is not the first step in preventing tragedies like those experienced by the families in the study, said Ackerman. If adults who carry the mutation know they have it, they can make informed decisions about whether or not to marry another person who is also a carrier.
There are still challenges ahead. For children who have inherited the mutation and are at risk of sudden death, the only solution to prevent it is an implantable cardioverter defibrillator (ICD), which can be extremely expensive. Ackerman said his team is working to understand more about the causes of gene duplication so that a drug can be developed to prevent it, a treatment that would be much more accessible.
“We are going fast and furious to try to solve this for this Amish community,” he said.
But for now, Ackerman hopes the discovery will provide a closure to families that have lost loved ones.
“We have finally discovered the curse of sudden death for the Amish community and now they have peace of mind about the reason,” he said.