Case closed? Genetic testing provides insight into unexplained sudden deaths of Amish children

An Amish family suffered a sudden and tragic event when one of their children died suddenly. The child wasn’t doing anything dangerous or unusual, but still died while playing. Within a year, another of their children suffered the same fate. Six years later, it happened again. And again merely two years after that. The cause of these sudden deaths was a mystery, as the autopsies and analysis didn’t turn up anything unusual. In fact, the children’s hearts appeared to be normal, and while researchers suspected the RYR2 gene could be the culprit, they didn’t see any unusual mutations upon analysis.

The medical examiner’s office reached out to a specialized lab at the Mayo Clinic that researches exactly this type of unexpected death, but the researchers were stumped as well. In the decade that followed, other doctors and experts from around the country were reaching out to the lab regarding other Amish families who were experiencing similar tragedies, all looking for answers and solutions.

In the beginning, researchers needed to analyze a single gene at a time. They were focusing on RYR2 from the very start, as single nucleotide substitutions in the gene were known to have been the cause of death in a different sudden death syndrome related to physical activity. Because of this, RYR2 was under the microscope, so to speak. At the time, however, no abnormalities within the gene were discovered.

Still, in the years that followed, technology went through significant advances. When two siblings died more recently, the research team had new and improved tools at the ready – and they have now solved the mystery.

They were on the right track with the focus on RYR2, but it turns out that while RYR2 was to blame it was in a much different way than they had guessed. Not just one base pair was at fault, rather a homozygous duplication involving approximately 26,000 base pairs of intergenic sequence in the 5’UTR/promoter region and exons 1 through 4 within the RYR2 gene was the cause. This discovery was made possible thanks to a special analytical method that can detect where entire genes or segments of genes could have been duplicated.

The research team, in findings published in January 2020 in JAMA Cardiology, found these exact mutations among four siblings from two seemingly unrelated Amish families. These families are carriers for the recessive RYR2 mutation that only seems to cause problems when a child inherits two copies of the gene, one from each parent. Individuals carrying only one copy of the mutated gene appear to be healthy.

Now that this is a known genetic biomarker, not only do the families have the answers they have so desperately been seeking but there are now actions they can take to prevent future sudden deaths from happening. For those who have inherited two copies of the gene and are at risk, an implantable cardioverter defibrillator (ICD), while expensive, can treat this condition.

Individuals can also now be genetically tested for this mutation in the RYR2 gene. If adult carriers know that they are carriers, they can make informed decisions when it comes time to consider life events like marriage and reproductive planning.

The researchers are working on engineering blood samples into beating heart cells from two individuals with the condition, aiming to essentially create an in vitro cellular disease model. They hope that this will lead to future breakthroughs into the molecular and cellular mechanisms that contribute to the sudden death outcome.

You might also be interested in: 
Human Ryanodine Receptor 2 (RYR2) Elisa Kit from Innovative Research

References and Further Reading:

• David J. Tester, Hannah M. Bombei, Kristi K. Fitzgerald, John R. Giudicessi, Beth A. Pitel, Erik C. Thorland, Barbara G. Russell, Samantha K. Hamrick, C. S. John Kim, Carla M. Haglund-Turnquist, Christopher L. Johnsrude, Dianne L. Atkins, Luis A. Ochoa Nunez, Ian Law, Joel Temple, Michael J. Ackerman. Identification of a Novel Homozygous Multi-Exon Duplication in RYR2 Among Children With Exertion-Related Unexplained Sudden Deaths in the Amish Community. JAMA Cardiology, 2020; DOI: 10.1001/jamacardio.2019.5400
• No one knew why the kids in 2 Amish families were dying suddenly. Now researchers have some answers. CNN Health: 16 January 2020. 
• A mysterious cluster of deaths amongst Amish children has finally been solved. Popular Science: 14 January 2020.
• Genetic testing provides insights to sudden unexplained deaths in Amish community. ScienceDaily: 8 January 2020.