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Infinitesimal odds: A scientist finds her child’s rare illness stems from the gene she studies

  • Author: Pam Belluck, The New York Times
  • Updated: April 25, 2018
  • Published April 25, 2018

PORTLAND, Ore. — By the time her mother received the doctor's email, Yuna Lee was already 2 years old, a child with a frightening medical mystery. Plagued with body-rattling seizures and inconsolable crying, she could not speak, walk or stand.

"Why is she suffering so much?" her mother, Soo-Kyung Lee, anguished. Brain scans, genetic tests and neurological exams yielded no answers. But when an email popped up suggesting that Yuna might have a mutation on a gene called FOXG1, Soo-Kyung froze.

"I knew," she said, "what that gene was."

Almost no one else in the world would have had any idea. But Soo-Kyung is a specialist in the genetics of the brain — "a star," said Robert Riddle, a program director in neurogenetics at the National Institute of Neurological Disorders and Stroke. For years, Soo-Kyung, a developmental biologist at Oregon Health and Science University, had worked with the FOX family of genes.

"I knew how critical FOXG1 is for brain development," she said.

She also knew harmful FOXG1 mutations are exceedingly rare and usually not inherited: The gene mutates spontaneously during pregnancy. Only about 300 people worldwide are known to have FOXG1 syndrome, a condition designated a separate disorder relatively recently. The odds her own daughter would have it were infinitesimal.

"It is an astounding story," Riddle said. "A basic researcher working on something that might help humanity, and it turns out it directly affects her child."

Suddenly, Soo-Kyung, 42, and her husband Jae Lee, 57, another genetics specialist at OHSU, had to transform from dispassionate scientists into parents of a patient, desperate for answers.

Soo-Kyung Lee, right, and Yuna, who has a rare defect on the FOXG1 gene, have a FaceTime call with Lee’s parents in South Korea, at their home in Portland, Ore., May 23, 2017. Balancing the missions of science and motherhood, Lee, who had worked with the FOX family of genes for years, began doing what she was uniquely positioned to do: aiming her research squarely at her daughter’s disorder. (Ruth Fremson/The New York Times)
Yuna Lee, who has a rare defect on the FOXG1 gene, during playtime at Bridlemile Elementary School in Portland, Ore., May 25, 2017. (Ruth Fremson/The New York Times)

They were plunged into a fast-moving ocean of newly identified gene mutations, newly named diagnoses and answers that raise new questions. The newfound capacity to sequence genomes is spurring a genetic gold rush, linking mystifying diseases to specific mutations — often random mutations not passed down from parents.

New research shows that each year, about 400,000 babies born worldwide have neurological disorders caused by random mutations, said Matthew Hurles, head of human genetics at Wellcome Trust Sanger Institute. As sequencing becomes cheaper, more children will receive specific diagnoses like FOXG1 syndrome, doctors say.

Yuna is now a sweet-natured 8-year-old still wearing a toddler's onesie over a diaper. "Cognitively she's about 18 months," Jae, her father, said.

A major achievement would be getting Yuna to indicate when her diaper is wet. Or to stand when they prop her against a kitchen corner and remove their hands for a split second. "If Yuna doesn't fall down right away," Soo-Kyung said, "we consider that a success."

Shortly after Yuna's second birthday, Soo-Kyung traveled to Washington, D.C., to serve on a National Institutes of Health panel reviewing grant proposals from brain development researchers. At dinner, she found herself next to Dr. David Rowitch, a respected neonatologist and neuroscientist she knew only by reputation.

"She started to tell me what's going on with her daughter," recalled Rowitch, a professor and head of pediatrics at the University of Cambridge who was then at the University of California, San Francisco. He was stumped but offered to send Yuna's brain scans to "the world's expert" in neuroradiology: Dr. Jim Barkovich at UCSF.

Barkovich said Yuna's scans revealed "a very unusual pattern," one he had not seen in decades of evaluating brain images sent to him from around the world. Yuna's cerebral cortex had abnormal white matter, meaning "there were probably cells dying," he said, and the corpus callosum, the corridor across which cells in the left and right hemispheres communicate, was "way too thin."

Searching scientific literature, he said, "I found a gene that seemed to be expressed in that area and found that when it was mutated it caused a very similar pattern." That gene was FOXG1.

Yuna Lee, who has a rare defect on the FOXG1 gene, explores her mother’s closet after her bath in Portland, Ore., May 23, 2017. (Ruth Fremson/The New York Times)

FOXG1 is so crucial that its original name was "Brain Factor 1," said Dr. William Dobyns, a professor of pediatrics and neurology at University of Washington, who published a 2011 study recommending a separate diagnosis: FOXG1 syndrome. "It's one of the most important genes in brain development."

FOXG1 provides blueprints for a protein that helps other genes switch on or off. It helps with three vital fetal brain stages: delineating the top and bottom regions, adjusting the number of nerve cells produced, and "setting up the organization of the entire cortex," Dobyns said.

Long before Yuna was born, Soo-Kyung stumbled upon research she found fascinating, showing that mice missing both FOXG1 genes did not form brains. That would apply to humans, too. "There's nobody who is missing two copies of the gene," said Riddle of the National Institute of Neurological Disorders and Stroke. "They don't survive."

Soo-Kyung told Jae she wanted to someday study how FOXG1 drives brain development. "Then Yuna arrived," Jae said.

Now, studying mouse brains, the Lees have identified genes that interact with FOXG1, helping explain why one crippled copy of FOXG1 damages the corpus callosum's ability to transmit signals between hemispheres.

"We now understand how this gene works and why," Soo-Kyung said.

From left: Joon, 4, Soo-Kyung Lee, Yuna, 7, and Jae Lee spend time together with guitars at their home in Portland, Ore., May 23, 2017.  (Ruth Fremson/The New York Times)

Many mysteries remain. Individual FOXG1 mutations affect gene function differently, so one FOXG1 patient's symptoms can vary from another's. For example, Charles A. Nelson III, an expert in child development and neurodevelopmental disorders at Boston Children's Hospital and Harvard Medical School, evaluated two 10-year-old patients with mutations in different locations and markedly distinct levels of impairment.

Since patients like Yuna, with one dysfunctional and one functional FOXG1 gene, produce half the necessary FOXG1 protein, Soo-Kyung wonders if gene therapy could restore some protein or boost protein activity in the good gene.

But because FOXG1 is crucial so early in development, Rowitch said, "I don't think you can just go back when the baby's born and build the brain back up."

Soo-Kyung rarely used to mention her daughter to fellow scientists, but recently began thanking Yuna during presentations. "I was afraid every day that she might not be with me the next day," Soo-Kyung said, voice breaking. "But she's done amazing things that we wouldn't dare to dream. So, how can anyone say she will never be able to do this, she will never be able to do that?"

At night they carry Yuna upstairs to her giant crib, her body arching elastically. Carting her up and down is getting harder, so the Lees expect to move from the three-level, cliffside house they bought to be closer, for Yuna's sake, to the hospital and their labs. With breathtaking views of Mount St. Helens, it is an optimist's house, where it is possible to see beyond the horizon.

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