About 15 years ago, an Amish family in the eastern US was hit by an unexplainable tragedy -- one of their children died suddenly while playing and running around. Just a few months later, the same fate befell another one of their children. Six years later, they lost another child. Two years after that, another one.
The autopsies didn't offer any clues. The children's hearts appeared normal. The family had what they referred to as "the curse of sudden death." And medical examiners couldn't figure out why.
After the deaths of the first two children, a medical examiner who conducted the autopsies got in touch with researchers at the Mayo Clinic Windland Smith Rice Sudden Death Genomics Laboratory in 2004. Researchers at the lab had pioneered the concept of molecular autopsy, using genetic testing to understand the cause of death in sudden unexplained cases, and the examiner wanted to see if they could shed light on the mystery affecting the Amish community.
The team suspected that a gene called RYR2 could be the culprit -- mutations of the gene can cause a cardiac arrhythmic disorder that can lead to exercise-fainting spells, seizures or even sudden cardiac death. But when they analyzed the gene to check for mutations, nothing turned up.
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 reached out to the lab about other Amish families whose children had also died sudden deaths -- all looking for answers about this heartbreaking phenomenon.
Then last week, researchers at the Mayo Clinic lab reported a breakthrough, published in JAMA Cardiology. With the help of new technology that wasn't around when they first started looking into the case, the team learned that these Amish children had all inherited the same genetic mutation from both of their parents. And out of the 23 young people who had inherited the mutation, 18 had died sudden deaths.
"As we started building out the family structure, it became apparent to us that this was most likely a recessive disorder," David Tester, the lead scientist on the case, told CNN. "With more information and more technological advancement in terms of being able to look at genes, we were able to put this puzzle together."
The children likely had a common ancestor.
Turns out, it was RYR2 -- the gene the researchers had suspected all along. But there wasn't just one mistake in the gene. More than 300,000 base pairs in the gene had been duplicated.
"We finally figured it out that it was an autosomal recessive condition where both bad duplications came from both parents, and those children were unfortunate to get the double dose," Michael Ackerman, director of the Windland Smith Rice Sudden Death Genomics Laboratory, told CNN.
To develop the duplication that causes sudden death, a child has to inherit a mutated gene from each parent -- the chances of which are 25 percent. That four children in one family inherited the mutation and died sudden deaths 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 intermarry, Tester said. The two families studied in the report are seemingly unrelated, but because the children all had the exact same duplication in a gene inherited from both parents, Ackerman said that it's likely that they have a common ancestor.
Now that researchers know about this genetic marker, there are steps that medical professionals can take to prevent sudden deaths from occurring in other Amish children, Tester said.
"Having this genetic biomarker, we can now very easily test any individual for the presence of the mutation," he said. "Having that ability can potentially save lives."
Knowing who has the mutation and who doesn't is the first step to preventing tragedies like the ones experienced by the families in the study, Ackerman said. If adults who are carriers for the mutation know that they have it, they can make informed decisions about whether or not they should 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 on understanding more about what causes the duplication in the gene so that a medication to prevent it can be developed, a treatment that would be much more accessible.
"We're going fast and furious to try to get this figured out for this Amish community," he said.
But for now, Ackerman hopes the discovery will provide some closure to the families who have lost their loved ones.
"We finally have figured out the curse of sudden death for the Amish community and they now have peace of mind as to the reason," he said.
Courtesy of a colleague
Courtesy of a colleague
Tester DJ, Bombei HM, Fitzgerald KK, Giudicessi JR, Pitel BA, Thorland EC, Russell BG, Hamrick SK, Kim CSJ, Haglund-Turnquist CM, Johnsrude CL, Atkins DL, Ochoa Nunez LA, Law I, Temple J, Ackerman MJ. Identification of a Novel Homozygous Multi-Exon Duplication in RYR2 Among Children With Exertion-Related Unexplained Sudden Deaths in the Amish Community. JAMA Cardiol. 2020 Jan 8. doi:10.1001/jamacardio.2019.5400. [Epub ahead of print]
The exome molecular autopsy may elucidate a pathogenic substrate for sudden unexplained death.
To investigate the underlying cause of multiple sudden deaths in young individuals and sudden cardiac arrests that occurred in 2 large Amish families.
DESIGN, SETTING, AND PARTICIPANTS:
Two large extended Amish families with multiple sudden deaths in young individuals and sudden cardiac arrests were included in the study. A recessive inheritance pattern was suggested based on an extended family history of sudden deaths in young individuals and sudden cardiac arrests, despite unaffected parents. A family with exercise-associated sudden deaths in young individuals occurring in 4 siblings was referred for postmortem genetic testing using an exome molecular autopsy. Copy number variant (CNV) analysis was performed on exome data using PatternCNV. Chromosomal microarray validated the CNV identified. The nucleotide break points of the CNV were determined by mate-pair sequencing. Samples were collected for this study between November 2004 and June 2019.
MAIN OUTCOMES AND MEASURES:
The identification of an underlying genetic cause for sudden deaths in young individuals and sudden cardiac arrests consistent with the recessive inheritance pattern observed in the families.
A homozygous duplication, involving approximately 26 000 base pairs of intergenic sequence, RYR2's 5'UTR/promoter region, and exons 1 through 4 of RYR2, was identified in all 4 siblings of a family. Multiple distantly related relatives experiencing exertion-related sudden cardiac arrest also had the identical RYR2 homozygous duplication. A second, unrelated family with multiple exertion-related sudden deaths and sudden cardiac arrests in young individuals, with the same homozygous duplication, was identified. Several living, homozygous duplication-positive symptomatic patients from both families had nondiagnostic cardiologic testing, with only occasional ventricular ectopy occurring during exercise stress tests.
CONCLUSIONS AND RELEVANCE:
In this analysis, we identified a novel, highly penetrant, homozygous multiexon duplication in RYR2 among Amish youths with exertion-related sudden death and sudden cardiac arrest but without an overt phenotype that is distinct from RYR2-mediated catecholaminergic polymorphic ventricular tachycardia. Considering that no cardiac tests reliably identify at-risk individuals and given the high rate of consanguinity in Amish families, identification of unaffected heterozygous carriers may provide potentially lifesaving premarital counseling and reproductive planning.
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