In the Clinic
Hsiao-Tuan Chao, MD, PhD: A Little Girl Walks Into a Clinic...A Newly Identified Genetic Disorder
ARTICLE IN BRIEF
Through whole exome sequencing, Hsiao-Tuan Chao, MD, PhD, identified a de novo mutation implicated in hypotonia ataxia developmental disorder syndrome, a rare disorder involving global developmental delay, expressive speech disorder, and varying levels of learning difficulties in children.
In the summer of 2015, Hsiao-Tuan Chao, MD, PhD, happened to have an opening in her clinic during her residency in pediatric neurology at Texas Children's Hospital in Houston when a 4-month-old girl named Collette was brought in by her parents.
“Everyone thought she was fine when she was born,” recalled Dr. Chao, who at the time was studying Rett syndrome. “But at four months she wasn't rolling over. She had difficulty swallowing and holding her head up. And the thing that struck me most was that she was a very serious, calm baby.”
Dr. Chao wanted to have a whole-exome sequencing test performed, but the family's insurer balked.
“We know that with whole-exome sequencing for people with neurologic disorders, we can give you a diagnosis in 35 percent of cases,” Dr. Chao said. “That's huge, because without the test, we're often struggling to figure out what's going on. But it's still considered experimental by some insurers.”
The following March of 2016, she saw Colette again and still had no diagnosis or explanation to offer her parents for the little girl's continuing symptoms, despite extensive diagnostic testing. The following week, however, a 7-year-old boy, as part of the National Institutes of Health-funded Undiagnosed Diseases Network, was brought to the attention of Dr. Chao and other researchers at the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital.
Through the Undiagnosed Diseases Network, the young boy received whole-exome sequencing, which came up with a de novo mutation, never before been linked to a human disease, in the gene for early B cell factor 3 (EBF3). A member of a highly conserved family of transcription factors, the gene had been shown in vertebrate and invertebrate studies to be essential for neuronal development.
“I made a fruit fly that had only the normal human gene, and then another that had only the human gene with the mutation the boy had,” Dr. Chao said. “The one with the mutation didn't make it past an embryo. It was a very bad mutation.”
Dr. Chao and colleagues then identified two other children with similar neurodevelopmental symptoms — global developmental delay, expressive speech disorder, and varying levels of learning difficulties — and the same EBF3 gene mutation. A 5-year-old girl was described by her mother as a very serious girl. “She would not smile, even if she was laughing out loud,” she said.
The symptoms resembled those of the 4-month-old she had first seen in her clinic. She thought this girl may have the same condition.
After finally receiving permission from the girl's insurer to conduct whole-exome sequencing on Colette, Dr. Chao received the results back a month later.
“It was a slightly different mutation in the same gene,” she said. “So all of a sudden, from this one girl who made such an impact on me, I could finally give her parents an answer. It felt like fate. She could have been assigned to any other physician in our clinic, and the 5-year-old likewise could have been assigned to anyone else.”
Mentored by Hugo J. Bellen, DVM, PhD, the March of Dimes Chair in Developmental Biology at Baylor College of Medicine and a Howard Hughes Medical Investigator, Dr. Chao received a Neurology Research Training Scholarship funded by the AAN during its Annual Meeting in Boston in April. The scholarship is funding her continued research into EBF3 and transcriptional dysregulation of neural circuits in neurodevelopmental disorders.
In January, Dr. Chao was lead author of a paper in the American Journal of Human Genetics, with collaborators from the Undiagnosed Diseases Network and Baylor College of Medicine, describing the disorder which they believe is caused by the de novo variants in EBF3. Two other papers by other groups were published simultaneously. Altogether, 22 patients have now been described in the literature; the number of undiagnosed children and adults is as yet unknown.
“I think what's happening is that we need this transcription factor, which controls all different pieces of brain development,” Dr. Chao said. “One part controls facial expressions, which I think is why they tend to look so serious. A lot of this ties into motor control, including the difficulty with speech. If you can't control your tongue, your lips, you can't speak. And when they do acquire speaking, it's apraxic.”
Key features of the disorder include not only the seriousness and difficulty speaking but, commonly, normal perception and understanding.
“They seem to be hearing and processing language correctly,” Dr. Chao said. “Their ability to understand appears appropriate for their age, but they can't talk appropriately for their age. The pronounced difference between understanding and speaking is key.”
Some of the children, however, also present with features consistent with autism, Dr. Chao said, including repeated movements and difficulties interacting with people. “It doesn't seem to be all of them,” she emphasized.
The children's faces have an ovoid appearance, she said. Their muscle tone is low, and they typically have learning difficulties.
“These characteristics may seem subtle on their own,” Dr. Chao said. “But they stand out when you see them all together.”
Formally named hypotonia ataxia developmental disorder syndrome (HADDS), the disorder is now best treated with therapy, she said.
“You work with them so they learn to sit up and swallow, so they can walk and speak,” Dr. Chao said. “The intelligence of these children may be underestimated because of their difficulties with spoken language, and they don't make the strong facial expressions you would expect. We need to involve neurologists and geneticists much earlier. We don't know how many other children out there have this genetic disorder but have never been diagnosed.”
When Dr. Chao broke the news to Colette's family, she said, “We cried a little, we laughed a little. I showed them the data. The message was, because we have an answer, I could tell them there are other people with this, and they're up to 16 years old. Before then it was a black box. We didn't know if she would ever be able to independently walk, or if she would decline. Most of the 22 other patients are walking, and several are able to speak. Most appear to understand verbal communication appropriately for their ages.”
The speed with which progress is being made astonishes her.
“Huda Zoghbi and her team spent 16 years to find the genetic cause for Rett syndrome in 1999,” Dr. Chao said. “Now that we've gone through the genomic revolution, we diagnosed these children with HADDS in less than six months. I think it's pretty amazing.”