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16 Jul 2025
When Noah Simonetti was 10 months old, he had an average day. He went to daycare; his parents picked him up, had dinner and put him to bed. Everything was fine.
At 4 in the morning, Noah’s mother, Kathleen, heard something strange over the baby monitor, so she checked on him.
Noah was blue. And he wasn’t breathing.
Kathleen put Noah on the floor and started CPR while her husband, Steven called 911. When the paramedics arrived, they had to shock Noah twice with a defibrillator to restart his heart.
At the hospital in Stony Brook, New York, doctors stabilized Noah. By the next day, he was doing well again, which delighted and confounded his care team. What happened? And why?
After a few days in the pediatric intensive care unit (PICU), Noah seemed fine, so his doctors prepared to release him from the hospital. Then, one of them saw the readout from the ambulance’s patient monitor. It showed that Noah had ventricular fibrillation, an arrhythmia that’s rare in children. Instead of sending Noah home, his doctors transferred him to Columbia Children’s Hospital in New York City, where they began a series of tests to determine what happened.
None of those tests provided an answer, so doctors decided to place an implantable cardioverter defibrillator (ICD) into his abdomen “as an insurance policy,” Kathleen said, in case he experienced more heart trouble.
“At that time, that was their only plan.”
The first genetic test: Cardiomyopathy and arrhythmia panel
Noah recovering in the hospital after ICD surgery
One of the tests Noah’s doctors recommended was a genetic test.
This first genetic test was a targeted panel focused on genes related to the heart. The results were inconclusive, including a variant of uncertain significance (VUS). VUS occur when testing identifies a genetic variant, but it’s unclear whether that variant is linked to a health condition. Kathleen had variants on her genetic test that overlapped with Noah’s, but no heart trouble, so doctors assumed the variants didn’t indicate a genetic cause for Noah’s cardiac arrest. “They left it at that,” Kathleen said.
As Noah recovered, the Simonettis continued to take him to specialists and worked to keep him healthy and safe. Pretty soon, he was able to return to daycare.
Another cardiac arrest leads to a different type of genetic test
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Noah in the hospital holding his father’s hand
The week after Christmas 2022, when Noah was 18 months old, he had a cold. Nothing major, Kathleen said. “He was just a little extra tired that day.” He was also breathing heavily, so the Simonettis decided to take him into urgent care, where the doctors tried to remedy his heavy breathing with steroids.
The steroids had no effect, so the clinic advised the Simonettis to go to the hospital. At that point, Noah was stable. “We almost thought they were joking,” Kathleen said when they required the family to take an ambulance. “At the time, we thought that was too much.”
Within an hour of arriving at the hospital, Noah was in respiratory distress. When doctors tried to intubate him, he went into cardiac arrest. Over the next 6 hours, Noah experienced two more cardiac arrests.
Noah’s doctors told the Simonettis to call their families. They didn’t think Noah was going to make it. Thankfully, Noah pulled through, but with extensive heart damage.
After 7 days on a ventilator and 25 days in the PICU, he had to relearn how to walk, talk, sit and eat. “He was only 18 months old then, so he’d just learned how to do all those things anyway,” Kathleen said.
Doctors still couldn’t tell the Simonettis why Noah had cardiac arrests, so Kathleen and Steven decided to do their own investigation. They asked for further genetic testing even though doctors said they’d already genetically tested everything related to Noah’s heart condition.
Noah’s doctors mentioned an option called exome sequencing, which involves testing an individual’s entire exome–the protein-coding regions where most disease-causing variants live—for genetic variations that might cause disease. This differs from genome sequencing, which sequences an individual’s entire genetic information. The Simonettis agreed to the test—anything to figure out why Noah’s heart was failing.
When the results arrived in June 2023, right after Noah’s second birthday, they revealed a variation in his PPA2 gene that causes sudden cardiac failure.
PPA2-related mitochondrial disease is a recessive condition, which means that Noah received one abnormal copy of the gene variant from his mother—an inheritance identified by the first genetic test—and one abnormal copy from his father. Steven’s initial genetic testing hadn’t revealed this gene variant, but further tests found he was also a carrier.
Finally, the Simonettis had their answer.
Understanding PPA2 deficiency
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Noah
PPA2 mitochondrial disease is a rare condition that affects the energy in the cells of the heart, which can reduce oxygen levels, cause organ damage and lead to sudden cardiac arrest. Most cases are diagnosed after an individual passes away.1 First described in 2016, PPA2 deficiency can be particularly lethal in individuals younger than 2 and teenagers exposed to small amounts of alcohol.2,3
Researchers know that viral illnesses and alcohol are sudden cardiac arrest triggers for people with the PPA2 variant, but they don’t yet know why. Some patients have neurological symptoms like neuropathies and muscle weakness, and some experience kidney and liver problems.
With a genetic diagnosis, the Simonettis could now ask precise questions of Noah’s care team, take preventive measures for his health and connect with other PPA2 families for support.
A treatment plan comes together
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Noah recovering in the hospital
Noah’s doctors quickly admitted they knew little about this rare condition and began working with Noah’s other specialists to devise a plan.
There’s no treatment for PPA2 deficiency. Patients and their caregivers must manage viral illnesses and avoid alcohol and dehydration. For the Simonettis, that means making sure no alcohol or other fermented substances, like vinegar, are in Noah’s food and helping him stay as virus-free as possible. The only other recommended precaution is inserting an ICD, which Noah received during his first hospital visit.
Noah’s care team created an emergency management plan so that whenever Noah gets sick, even with something minor like a cold, he can go to the emergency room and receive immediate care. Instead of managing most childhood illnesses at home, the Simonettis go straight to the doctor. “Our local hospital is very familiar with him now,” said Kathleen, “When we come in, they’ll give him fluids, do labs and monitor him to make sure his heart is handling any condition okay.”
There’s a shortage of studies about PPA2, so the Simonettis err on the safe side by feeding Noah a restrictive diet that avoids all fermented foods and artificial flavorings. They remain vigilant against accidental doses of alcohol–from medication or vanilla extract, for example.
Noah’s family finds a way forward
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The results of Noah’s genetic tests turned the Simonettis’ lives upside down, but the results also gave them the certainty they needed to protect Noah’s fragile heart. Now, they can also take steps to protect Noah’s sibling.
When Noah’s exome sequencing results came back, Kathleen was 6 months pregnant with his sister, Sophia. Knowing about PPA2 caused the Simonettis to ask for an amniocentesis—a test on amniotic fluid that can reveal genetic anomalies in a developing fetus—to determine if the baby also had PPA2 deficiency. If she tested positive, Kathleen would have had a very monitored pregnancy and a special delivery with specialists nearby.
So far, genetic testing has shown that Sophia didn’t receive a PPA2 genetic variation from her mother. It’s still unknown if she received one from her father. Because PPA2 deficiency is a recessive condition, the Simonettis know it won’t affect her directly even if tests someday show she is a carrier.
Noah’s test results also impacted both branches of his extended family. After receiving the results, the Simonettis encouraged their family members to get tested. “A lot of them stalled with that, probably thinking, ‘What are the odds that we have the variation too?’”
Of the 12 people tested by the two families, 10 have tested positive as carriers of the PPA2 variant.
An advocate for more genetic testing
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Noah and Sophia Simonetti
The first time Noah’s heart failed, Kathleen asked his doctors, “‘If he passed away, what would you have called it?’ They said they would probably have called it sudden infant death syndrome (SIDS).” She wonders how many infant deaths are classified as SIDS when there could be an underlying genetic cause.
“It’s something that’s going to affect us forever,” said Kathleen, “but we’re so grateful to finally have an answer. We’ve been able to connect with several other families affected by the condition, and it’s been very helpful. Unfortunately, several of them have lost multiple children due to this disease.”
When they consented to testing, Noah’s doctors asked Kathleen and Steven if they were willing to find out the results no matter how bad they were. They said yes. “We got results—not the ones we wanted—but I think it was definitely for the best,” Kathleen said. “If we hadn’t received the PPA2 diagnosis, I don’t know if Noah would still be with us.”
“When it comes to getting genetic tests, everyone’s going to be different, but I say, ‘Do it.’” Kathleen’s experience makes her think that genetic testing should happen sooner and be more affordable, and that people shouldn’t have to have a family history to get it done. “We just want to get the word out,” she said, “so maybe someone else can be helped.”
Today, Noah is 3 and a half years old and thriving. He loves reading, dinosaurs, soccer and his little sister (most of the time). He just started preschool. He’s relearned all the skills he lost during his second cardiac arrest, and his heart has fully recovered.
“When you see him running around and playing, he looks 100 percent normal,” Kathleen said. “It’s hard to understand that [he has] a life-threatening condition.” Thanks to the information they learned from genetic testing, Kathleen said, “We can better protect Noah.”
Learn more about genetic exome testing on Invitae's website (now part of Labcorp).
References
- Genthe W, et al. Journal of the American College of Cardiology. 2023;24:102024.
- Kennedy H, et al. The American Journal of Human Genetics, 2016;99(3):674–682.
- Gómez González C, et al. Gene. 2024;916:148437.