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Rare Disease Day 2023
Forming a new rare disease community
Members of the CTCF community at the Georgia State Capitol in 2020.

Members of the CTCF community at the Georgia State Capitol in 2020. Courtney is on the left, while Dr. Li is on the right.

It started with an email from a persistent mom, who was worried about her son’s seizures. Courtney, a high school teacher in Walton County, Georgia, unexpectedly found allies at Emory. (To shield her son’s future privacy, this article uses her first name only.)

They ended up creating a new community, recruiting families affected by a rare genetic mutation from across the country and around the world. Their goal: to provide parents and clinicians with the accurate information Courtney had lacked four years ago. 

In 2019, several weeks after his birth, Courtney’s son had begun to experience seizures, and the doctors they’d seen were slow to react. They first thought he was displaying signs of acid reflux. Courtney, who works in special education, had experience with kids with learning differences. But her son’s seizures were the first she had witnessed. 

After pushing for more information and then agreeing to pay out-of-pocket* for genetic testing, she and her husband received an extensive report, but they needed help making sense of it. The report said that her son’s genome carried a mutation in the gene encoding the protein CTCF. However, no information was available about what parents might expect. Searching online, Courtney found references to Victor Corces, an Emory geneticist who had published several papers about CTCF.

There were 39 cases known in the whole world,” she says. “I was just a mom asking for help. I didn’t know what CTCF was.”

When she contacted Corces, Courtney was surprised to see an answer come back the same day. Corces did have plenty of experience studying CTCF’s functions, both in Drosophila fruit flies and in mice. He was willing to help, although he wasn’t a medical doctor.

“He was my only ally at the time,” she says.

From Corces, she learned something about what CTCF does. Picture DNA in the cell nucleus as an unruly pile of extension cords in the garage. CTCF organizes the DNA into manageable loops. Tinker with CTCF, and genes shaping brain, heart or skeletal development might be on or off at the wrong time or in the wrong cells. That might explain why some people with CTCF mutations had intellectual disability, cardiac defects or changes in their craniofacial structure.

Learning more together

In an initial effort to gather information about CTCF mutations, Courtney wrote hundreds of emails. Many were to genetics specialists, asking them to share her information with their patients. She participated in Facebook groups for parents of children with special needs, and eventually started her own. In this way, she found her first compatriot, a mom in New York whose child also had a mutation in CTCF. Other families she found had received diagnoses years before, but also felt alone. Once they met others dealing with the effects of similar mutations, they could compare notes. But the symptoms weren’t the same in each individual, which was confusing.

“When you’re dealing with a genetic mutation that nobody understands, there’s nothing better than reaching out to someone else who knows what you’re going through,” Courtney says.

Soon after their email exchange, Corces conferred with Hong Li, a medical geneticist at Emory, at a Department of Human Genetics retreat. Courtney’s son was already scheduled to see Li at the Emory genetics clinic in two weeks. Li was intrigued, even though information about the clinical effects of CTCF mutations was limited. Meeting the family confirmed her interest.

“I was very impressed by the connections she had already made,” Li says. “I said: ‘Maybe we can learn more about this disease together.’”

Li eventually recruited Gabriella Valverde de Morales, an Emory genetics counseling student, to systematically gather information about people with CTCF mutations. Hsiao-Lin Wang, a postdoctoral fellow in Corces’ lab, joined in too. Together with the contacts Courtney had made via social media, it began to feel like a community.

“Dr. Li will answer my phone call when we are in the emergency department at midnight, and will tell the other doctor what’s going on,” she says. “It really helps, because most doctors — even pediatric neurologists — have not encountered someone with a CTCF mutation.”

For Rare Disease Day in 2020, the group visited the Georgia state capitol to advocate for greater attention to rare diseases. Researchers and families from around the world recently held a Zoom conference, with plans for an in-person gathering next year.

Li and colleagues recently published a paper in the American Journal of Medical Genetics describing more than 100 people with CTCF mutations, recruited from North America, several European countries, Australia and Israel. Most have some form of intellectual disability or developmental delay, such as motor or speech delay. While some are severely affected, a few attend college. One distinctive aspect of the paper: a face. Using computer modeling, the authors created an image of typical patient’s facial features, which could facilitate clinical recognition and diagnosis.

Some families report cardiac defects, cleft palate or hearing loss, but these are not universal features of CTCF-related disorder. The group has developed a list of tests and examinations newly diagnosed patients should undergo to catch potential problems. Armed with this information, one family discovered their child had a heart defect and was able to intervene before it became severe.

And through research by Hsiao-Lin Wang in Corces’ lab, Courtney now has some answers — still incomplete — to her original questions about why her son experiences early onset seizures and how best to control them. Her son’s unique mutation in CTCF appears to perturb the activity of sodium channel genes, which control electrical signals in brain cells. This information could guide discussion with neurologists about optimal medications, she says.

In the fall of 2022, Li and Corces obtained a grant from the National Institute of Dental & Craniofacial Research to study in greater detail how the effects of CTCF mutations are connected with the protein’s function. Li says she wants to examine other factors that may influence the symptoms a child with a CTCF mutation may experience, such as cleft palate or seizures.

* The family later received a grant from the testing company GeneDx’s Odyssey program for exome sequencing, which is often not covered by insurance.

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