Hillary Savoie wanted clear answers. Instead, the genetic testing results for her 4-year-old daughter, Esmé, sent her reeling. “I’m pale. The bags under my eyes are purple,” she wrote in her blog started when Esmé was a baby. “My lips are drawn tight in a thin line.” Ever since the little girl came into the world in 2011, limp, blue, and struggling to breathe, doctors had been searching for the cause of her problems. They were certain the answer was hidden in Esmé’s DNA, the genetic code comprising more than three billion letters that help determine our basic makeup, from health risks to what we look like. A genetic test performed when she was almost 2 years old revealed a variant on one of Esmé’s genes—“one tiny letter switched out for a second letter,” Ms Savoie described it—which doctors thought might explain her delayed walking and talking, and epilepsy. The findings gave the family an answer and a community. Esmé had a variant in the PCDH19 gene. Ms Savoie threw herself into PCDH19 research and friendships with families of other PCDH19 children. A later DNA test, in 2015, upended that. The lab no longer considered that variant a culprit in Esmé’s condition after all. It now pointed to a variant of a different gene that hadn’t been flagged before because it wasn’t part of genetic testing at the time. Two other patients with epilepsy and intellectual disability had variants on this other gene, the report said. One of them had died. “The ground kept shifting,” says Ms Savoie. “It was a crisis of identity, as well as a crisis of faith in science to tell us something we could rely on.” Esmé’s genetic code hadn’t changed. But the interpretation of new and rare gene variants does, frequently, sometimes in ways that can change a person’s treatment strategy and prognosis. For Esmé’s family, the report still wasn’t the final word.
DNA testing has created a wealth of information for patients and doctors. Because it generates so much new data, the medical world is still trying to understand what it all means, bringing uncertainty and anxiety for many families. “We are in a period of drastic evolution in our field,” said Heidi Rehm, Chief Genomics Officer at Massachusetts General Hospital in Boston, who is involved in DNA interpretation efforts, including one to cull gene associations no longer considered accurate. Some genetic testing, like that performed on the millions of new-borns tested with drops of blood taken from their heels, has been around for decades. Commercial genetic testing surged after scientists announced in 2003 they successfully sequenced the human genome. Improvements in technology allowed for the testing of many genes at the same time. Prices of tests plummeted.
Last year, a study published in the journal Health Affairs estimated there were approximately 75,000 genetic tests used by doctors on the market, with about 10 new ones released every day. (Direct-to-consumer tests weren’t included in that count.) Doctors use genetic tests to help inform treatment for rare conditions, cancer and heart disease. They find themselves peppered with questions from consumers who want to understand the results of their home-testing kits. As more people have their DNA tested, and rely on the results as gospel, the potential for reinterpretations is having far-reaching consequences. Researchers at the University of Texas Southwestern Medical Center, including a child neurologist, published a study last year reviewing more than 300 epilepsy cases. It found nearly a third of the children had a change in diagnosis based on new genetic data that emerged in the previous five years. Researchers recommended parents review gene tests performed on children with epilepsy at least every two years to keep up with changes. In a paper this year, researchers reviewed data for 33 genes routinely tested to diagnose a genetic condition involving thickening of the heart muscle that can lead to sudden death. Of those genes, they found 22 had either limited or no evidence for causing the disease, said Jodie Ingles, Associate Professor at the University of Sydney and lead author on the paper. Dr Ingles points to the case of a family that underwent testing for a gene associated with a heart disorder after a young son’s sudden cardiac death. A brother was found to have a variant. He was implanted with a defibrillator and received two shocks. But doctors later determined the variant wasn’t linked to the disorder after all. The case, reported in medical literature, haunted her, said Dr Ingles, who wasn’t personally involved. “We have to be sure. There is so much potential for harm if we get it wrong.”
At first, the Savoies resisted genetic testing. After Esmé’s difficult birth, Ms Savoie says she and her husband, André, didn’t have time to think about “the mystery of Esmé’s DNA.” Their new-born spent a week in the neonatal intensive care unit while doctors tried to wean her off oxygen and get her to eat. The parents wanted to take her home as soon as possible. Ms Savoie had been enrolled in a PhD programme in communication and rhetoric and was teaching a writing course at Skidmore College. She eventually completed her degree but was unable to keep teaching. She didn’t want to leave Esmé, who had frequent seizures, and became an advocate on her daughter’s behalf. “We want to let this observant, quiet and solemn child show us who she is,” Ms Savoie wrote about that early period, “regardless of what is written in her genes.” Mr Savoie, an architect, initially didn’t care what the issue was called. “I knew we would deal with whatever it was,” he said. Months later, “I grew to change my opinion about testing.” At 3½ months old, Esmé went into cardiac arrest. Ms Savoie raced into the emergency room with her child cradled in her arms. Doctors asked if the baby had any genetic conditions. “I wanted to tell them something to help, but I didn’t have a label,” Ms Savoie said. In the hospital, a geneticist went over the types of tests clinicians recommend. They started with a test for 22Q11, a deletion on chromosome 22 that can cause heart problems and developmental delays. The test was negative. Doctors then ordered a DNA microarray, state of the art at the time, which searches a larger swath of DNA. Six weeks later, the geneticist called. The test results didn’t turn up anything unusual either. Ms Savoie started to realize “the limits of what genetics could tell us.” They took a pause from testing. Esmé was fragile. She vomited repeatedly and wasn’t gaining weight. They needed to tend to her daily medical problems.
In August 2012, when Esmé was 20 months old, the couple decided to try testing again. Her seizures required frequent trips to the hospital. She was fed through a tube and didn’t speak. She was also energetic and curious, splashing in the small pool in the backyard and rolling around the house instead of walking. Ms Savoie took Esmé once a month to Boston Children’s Hospital, a 3-hour drive from their home in Troy, N.Y., to see specialists—in immunology, pulmonology, cardiology and other fields. The family hoped finding the correct gene might lead to a treatment. Doctors told her about a new test for 36 genes associated with different forms of infantile epilepsy. It was expensive and not widely available. A hospital committee determined Esmé should get it. Just shy of Esmé’s second birthday, the doctor called to say the test found a variant in one of the epilepsy-causing genes: PCDH19. Esmé didn’t have all of the symptoms associated with the condition, but the family grabbed onto it. “It was the first thing in all of our testing that started to look like an answer,” Ms Savoie says. Pursuing answers for Esmé was difficult. “It was really lonely. So lonely. Now I had something on a piece of paper that says your child has this,” she said. It gave her hope that “Maybe there are other kids like her out there, and we just haven’t found them yet.” Ms Savoie found an online support group started by parents of children with PCDH19 gene variants and embraced that world.
On a visit to Boston, she and Esmé went to a barbecue at a family’s home with four other children in the PCDH19 community. Ms Savoie flew to meetings with researchers. In 2013, she started a foundation and raised money for PCDH19 research. The foundation helped fund a project in a lab using zebrafish. She and her husband took Esmé to see the fish. Ms Savoie made “intense friendships” and engaged in daily conversation with some mothers. For two years, the community was her main emotional support. She met many of the children and made a video with them to raise awareness. But as more children were diagnosed, Ms Savoie noticed that the difference between Esmé’s symptoms and those of the others was more pronounced. One child was learning to ride a bike. Another loved singing and climbing on the playground. At the age of 4, Esmé couldn’t do any of those things. Jozef Gecz, a researcher at the University of Adelaide in Australia, whose lab discovered disease-causing variants in the PCDH19 gene, met Ms Savoie at a 2013 group meeting. He too realized Esmé was different than many of the other children. He tried to persuade Ms Savoie they needed to keep looking. Ms Savoie was torn. Having found a community, she wanted to stay in it.
In 2015, labs were starting to more widely offer “whole exome sequencing,” which sequences large amounts of DNA, particularly in sections where many disease-causing genes are located. Esmé’s blood was sent for testing. Ms Savoie read the results. They kept her up at night. Her daughter’s PCDH19 variant, previously classified as of unknown significance, was now ruled likely not to be disease-causing. And Esmé had a variant in a different gene, called SCN8A, that was so new it hadn’t been on her previous test. It now seemed to explain more of Esmé’s symptoms. SCN8A cases were still very rare. Scientists had only recently discovered some variants were associated with epilepsy. Esmé’s report described two previous cases, including one who died. The one who died, she learned later, was a child. In the wake of the new interpretation, Ms Savoie considered the PCDH19 world she had been inhabiting and felt, “I no longer had a claim to that community.” The foundation she set up stopped funding future PCDH19 projects and started fundraising for SCN8A research. Tracy Dixon-Salazar, who is the Director of Research and Strategy at a foundation that focuses on Lennox-Gastaut Syndrome, a type of epilepsy that her daughter has, said frequent variant reinterpretations can cause hurt feelings when people move between different groups. “They experience everything at 10 times the emotional impact. That’s on top of this horrific disease their children have.” Elizabeth Sucher, whose 15-year-old daughter, Evelyn, has a PCDH19 variant and participated in a photo shoot with Esmé to raise awareness of children with disabilities, said she was “thankful for the personal relationship. I am of the mindset people have to do what they have to do. I don’t care about the mutation type or name,” she said. “You have to understand when you are dealing with kids with any complicated medical situation, everything is fluid.”
Ms Savoie connected online with a group of parents whose children all had SCN8A mutations. Esmé’s medication didn’t change, but because of risks associated with the SCN8A variant, her parents pursued cardiac monitoring. At first, Ms Savoie held back from sharing Esmé’s story. She was concerned about meeting new people, getting attached, and the diagnosis changing again. She told the parents that doctors weren’t sure yet if the SCN8A variant was the cause of Esmé’s condition. Parents told her an official diagnosis didn’t matter. “We are all going through the same thing, trying to save our child’s life,” said Dianely Cabrera, whose 4-year-old son, Max, has an SCN8A variant. Ms Savoie had a measure of peace. Even this wasn’t to last. In 2016, the family received a new report from the lab that had done Esmé’s whole exome sequencing a year before. Esmé’s genetic results had been reinterpreted—again. Esmé’s SCN8A variant was still considered of unknown significance. But now they also found two other gene variants, labelled “likely pathogenic” and “pathogenic,” or disease-causing, which hadn’t been previously known. Each time Esmé seemed to have a label, it was later taken away. Twice, Ms Savoie found a genetic home, only to feel she no longer belonged. As more people get tested, the lab might change its interpretations again, Mr Savoie said. Any one of Esmé’s four genetic mutations—separately or perhaps in concert—might eventually turn out to be disease-causing. Mr Savoie said his wife didn’t want to leave the SCN8A community with which she now closely identified. “She did not want to give up on the possibility that one of these genes was the cause,” he said. “And she did not want to let go of people she cared for.” Shelley Frappier, whose 5-year-old son, Nico, has an SCN8A diagnosis, and who works as a volunteer in Ms Savoie’s foundation, urged Ms Savoie to stay. To her, what binds the parents isn’t the particular disease-causing gene variant but the desire to save their children’s lives. “Every night, I give my little boy a kiss at night and don’t know if that’s the last one,” said Ms Frappier. “We all live with that fear.” Ms Savoie decided to continue her work with SCN8A, even if any discoveries seemed unlikely to benefit Esmé. She also joined Facebook groups for people with variants in the two new genes listed in Esmé’s latest report. She stays in touch with some members of the PCDH19 community.
Esmé attends school from 8:30 a.m. to 1 p.m., participating in a small class where she has her own nurse. She works on reading and math, speech therapy and music therapy. After school, she has therapy in a pool and an additional school session with a teacher at home. When the weather is nice, she goes outside in her wheelchair. She blows bubbles and plays with toy cars. She is a fan of the movie “Coco” and the Muppets. Esmé makes sounds, but is often difficult to understand, even for her parents. In January, Ms Savoie arrived at Boston Children’s Hospital with 8-year-old Esmé. Dressed in a purple sweatshirt and black leggings, she sat on her mother’s lap, her eyes darting to the bright fish in the giant aquarium in the lobby. A long day of doctor appointments lay ahead, but Ms Savoie stopped to chat with an expert in epilepsy genetics she knew, Annapurna Poduri. A new genetic testing opportunity was available, she told Dr Poduri. At a recent meeting of rare-disease advocates, a lab offered to test Esmé’s DNA again. More information and improved technology offered the possibility of yet-another interpretation of Esmé’s genes. The seizures were getting more difficult to control, Ms Savoie said, and she was leaning toward doing it. “What we know still doesn’t explain Esmé,” she said. Dr Poduri watched Esmé, chewing contentedly on her mother’s scarf. The girl’s blue eyes blinked back. They decided to move ahead with the testing. “I tell all the families,” the doctor said, “this is what we know now, but it is going to change.”
Credit: Dockser Marcus for The Wall Street Journal, 17 May 2019.