The autopsies offered no clues. The children's hearts seemed normal. The family had what they called "the curse of sudden death." And the coroners couldn't figure out why.
Following the death of the first two children, a coroner who conducted the autopsies contacted researchers at the Mayo Clinic's Sudden Death Genomics Laboratory in Windland Smith Rice in 2004. Researchers at the laboratory pioneered the concept of molecular autopsy. using genetic testing. to understand the cause of death in unexplained sudden cases, and the examiner wanted to see if they could clarify the mystery affecting the Amish community.
The team suspected a gene called RYR2 could be the culprit – mutations in the gene could cause an arrhythmic cardiac disorder that could lead to fainting, seizures or even sudden cardiac death. But when they analyzed the gene for mutations, nothing appeared.
The case remained cold for over a decade. Over the years, pediatric cardiologists and genetic counselors from other parts of the country have contacted the laboratory about other Amish families whose children had also died suddenly – all seeking answers about this heartbreaking phenomenon.
"When we started building the family structure, it became clear to us that this was probably a recessive disorder," David Tester, the lead scientist for the case, told CNN. "With more information and more technological advances in terms of ability to analyze genes, we were able to put this puzzle together."
The kids probably had a common ancestor
Turns out it was RYR2 – the gene that researchers suspected all along. But there was not just one error in the gene. More than 300,000 base pairs in the gene have been duplicated.
"We finally found that it was an autosomal recessive condition where the two bad duplications came from both parents and these children were unfortunate enough to receive the double dose," Michael Ackerman, director of Windland Smith's Laboratory of Sudden Death Genomics, told CNN. Rice .
To develop the duplication that causes sudden death, a child must inherit a mutated gene from each parent – whose chances are 25%. That four children in one family inherited the mutation and died suddenly is incredibly unfortunate, Ackerman said.
The Amish may be more vulnerable to recessive inherited conditions because they are descended from a small number of ancestors and tend to marry, Tester said. The two families studied in the report apparently are 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.
Discovery May Help Prevent Sudden Death
Now that researchers know this genetic marker, there are measures that medical professionals can take to prevent sudden deaths from occurring in other Amish children, Tester said.
"With this genetic biomarker, we can now very easily test any individual for the presence of the mutation," he said. "Having this ability can potentially save lives."
Knowing who has the mutation and who is not the first step in preventing tragedies such as those experienced by the families in the study, Ackerman said. If adults with the mutation know they have it, they can make informed decisions about whether or not to marry someone 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 avoid it is an extremely expensive implantable cardioverter-defibrillator (ICD). Ackerman said his team is working to understand more about what causes gene duplication so that a drug to prevent it can be developed, a treatment that would be much more affordable.
"We're going fast and furiously trying to figure this out for this Amish community," he said.
But for now, Ackerman hopes the discovery will provide some closure to families who have lost their loved ones.
"We finally discovered the curse of sudden death for the Amish community and they now have peace of mind as to why," he said.