To her family, Tatiana Legkiy looked completely healthy when she was born. But a pediatrician who listened to her heart heard something off. So within a few days of being born, she saw a specialist who did an echocardiogram and who, alarmed by the results, called an ambulance to take her to the hospital in Modesto, Calif.

From there, she was rushed to a hospital in San Francisco. The newborn’s heart was failing.

“We could hear her screaming as soon as the elevator opened,” Lana Legkiy, Tatiana’s mother, recalled.

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Clinicians there treated Tatiana and started medication that helped her heart pump. But while that emergency was ending, a years-long scientific search for answers was just beginning. Along the way, researchers would uncover an undiagnosed heart problem in Tatiana’s older sister, provide a new explanation for why Lana lost a prior pregnancy, and shed light on the unexpected ways in which disease-causing mutations can be inherited.

Heritable diseases — say Huntington’s, sickle cell anemia, or cystic fibrosis — are typically thought of as the result of a certain mutation in one gene. But sometimes, variants of a few genes collectively cause what are called “oligogenic” diseases.

This, it turns out, is what happened to the Legkiy family. Tatiana; her older sister, Anna; and the lost fetus each received rare mutations in three genes from their parents — two from their father, one from their mother — that together triggered the heart issues. Having one of those genetic variants, or even two, wouldn’t have caused serious problems. But the subtle nudges from each of the variants scooched them past a threshold into having unhealthy hearts.

“Each one of these, it pushes you a little closer to the cliff, until the point you get pushed off the cliff,” said Dr. Wendy Chung, a pediatric geneticist at Columbia University Medical Center, who was not part of the team studying the Legkiy family.

Tatiana
Tatiana in 2009 Courtesy Lana Legkiy

Tatiana arrived at the hospital over a decade ago, but the scientific quest only culminated recently, when a team of researchers from the Gladstone Institutes and the University of California, San Francisco, published a paper in Science laying out how they had teased apart exactly what was going on. Their discoveries were only possible because of advances in stem cell and genome editing wizardry that didn’t exist when Tatiana was born, and because of the encounter with a family whose children had all inherited the same confluence of mutations.

If only one of the children had had the heart issues, “you would never recognize that as a genetic cause,” said Dr. Deepak Srivastava, the president of Gladstone and a pediatric cardiologist at UCSF Benioff Children’s Hospital, who was one of the clinicians involved in Tatiana’s care years ago. “You might think it just happened sporadically.”

When Tatiana arrived at the hospital, clinicians discovered she had a condition known as left ventricular noncompaction, or LVNC. Her heart hadn’t matured as far as it should have; part of it appeared as if it were still developing in the womb, so it was having trouble contracting as strongly as it needed to.

As they searched for the root of the issue, members of the medical team examined the rest of the family. They found evidence of the same condition in Anna, then 4 years old. But her heart seemed to be compensating for the problem. Despite abnormalities in her heart, she had never shown any symptoms.

Clinicians also studied tissue samples from the pregnancy Lana had lost at 24 weeks, a boy who would have been about a year older than Tatiana. The team discovered that his heart had not developed properly, either.

Intriguingly, when doctors examined the children’s father, Andrey, they noticed an understated, adult-onset form of LVNC that had never caused any problems. That suggested the cause was genetic, but given the varying seriousness of the condition between the generations, they suspected that the cause was more complicated than the simple inheritance of a disease-causing gene from a father.

“It was curious that the kids had such a severe form, but the dad had such a mild form,” said Srivastava, the senior author of the Science publication. “We did think from the get-go that it was possible that maybe there was something coming from the mother that was making it worse.”

Within a few months, the team had started sequencing the family members’ exomes — the portions of the genome that contain the instructions for making proteins — in an effort to ferret out the genetic makings of the malady.

In 2014, while searching for disease-influencing variants of genes involved in the development of the heart, the team landed on three in the MKL2, MYH7, and NKX2-5 genes that Andrey and Lana’s three children all had.

The catch was that two of them — the variants of the MKL2 and MYH7 genes — came from Andrey, while the third was passed down by Lana. MYH7 plays a key role in the contraction of the heart, while the other two genes help choreograph the formation of the heart during development.

Legkiy family
The Legkiy family Courtesy Lana Legkiy

“Each of these genes, their function is disrupted in a given number of cells, but each one only causes a slight level of disruption,” said Casey Gifford, a Gladstone scientist and the lead author of the paper. “Your body, it seems, can tolerate one bad copy as long as it’s in isolation.” But together, she added, the mutations are capable of causing serious congenital heart problems.

Researchers have long suspected that oligogenic inheritance triggers many human diseases, particularly childhood conditions that don’t appear to be the result of environmental factors and can’t be otherwise explained. But they’ve had a difficult time verifying which combination of mutations is involved.

In this case, scientists turned to research tools that have only become available in the past few years.

In one line of experiments, they used the genome-editing tool CRISPR to create mice that had the same combination of mutations as the Legkiy family. Mice with all three of the variants had hearts that, like those of the children, appeared as though they hadn’t fully matured during embryonic development. (Animals with the two variants Andrey has similarly showed subtler signs of an abnormality.)

The researchers also converted skin cells from the family members into so-called induced pluripotent stem cells — restoring their ability to become other cell types — and then coaxed them into becoming cardiac cells. For the kids, they found that genes that are expressed during development were still “on,” indicating these cells were in a form of delayed development.

Researchers not involved with the investigation praised the work, noting just how many steps were required — and how long it took — to corroborate the genetic roots of the heart conditions. But they also said clinicians and research teams won’t be able to replicate the science for every case in which a hodgepodge of mutations is suspected of causing a disease.

“What I took away from this paper is that this burden of proof for this phenomena is very high,” said Nicholas Katsanis, a human geneticist at Northwestern University and Lurie Children’s Hospital of Chicago, who in 2001 made key discoveries about the different genetic underpinnings of a condition called Bardet-Biedl syndrome.

“The big question that’s in front of us is how to detect this type of variation amid the backdrop of the variation we all have,” he said.

It’s a question that researchers will have to wrestle with moving forward, but it feels quite far away from where Anna and Tatiana are now, at 15 and 11 and living in the Dallas area. They both have regular checkups with cardiologists, but are not on any medications or limited in any way, their mother said. Their hearts have matured to the point where the conditions they showed early in their lives are not such a worry anymore.

Tatiana’s heart, Gifford said, “just needed more time to catch up to what her body needed.”

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  • This article and many , many others are undeniable proof and corroborating evidence as to the lethal killing machines so named . The Antimicrobial Resistant Super Bugs . See the World Health Organization?s two hundred fifty seven pages of reports in the year of 2014

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