Most people who visit a doctor when they feel unwell seek a diagnosis and a treatment plan. But for some 30 million Americans with rare diseases, their symptoms don’t match well-known disease patterns, sending families on diagnostic odysseys that can last years or even lifetimes.
But a cross-disciplinary team of researchers and physicians from Washington University School of Medicine in St. Louis and colleagues from around the world has solved the mystery of a child with a rare genetic illness that did not fit any known disease. The team found a link between the child’s neurological symptoms and a genetic change that affects how proteins are properly folded within cells, providing the parents with a molecular diagnosis and identifying an entirely new type of genetic disorder.
The results, published Oct. 31 in the journal Science, have potential to help find new therapies for rare brain malformations.
“Many patients with severe, rare genetic disease remain undiagnosed despite extensive medical evaluation,” said Stephen Pak, PhD, a professor of pediatrics and a co-corresponding author on the study. “Our study has helped a family better understand their child’s illness, preventing further unnecessary clinical evaluations and tests. The findings also have made it possible to identify 22 additional patients with the same or overlapping neurological symptoms and genetic changes that affect protein folding, paving the way for even more diagnoses and, ultimately, potential treatments.”
According to Pak, about 10% of patients with suspected genetic disorders have a variant in a gene that has not yet been linked to a disease. His career has been focused on solving such medical mysteries.
Pak and author Tim Schedl, PhD, a professor of genetics and a co-director of the model organisms screening center at WashU Medicine, use tiny roundworms called C. elegans to assess whether specific genetic changes found in undiagnosed patients are responsible for their symptoms. With funding from the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health (NIH), they and a team of researchers at WashU Medicine have committed to solving more such cases.
For this study, they teamed up with researchers and doctors from more than a dozen institutions across North America, Europe, India and China to identify the cause of a cluster of clinical findings in a boy from Germany, and other similar cases. The German patient had an intellectual disability, low muscle tone and a small brain with abnormal structures. Doctors also found changes to the CCT3 gene, so Pak’s team set out to determine if it could be the cause of the patient’s condition.
C. elegans has counterparts to about 50% of human genes, including the CCT3 gene, which is known as cct-3 in roundworms. Weimin Yuan, PhD, a staff scientist in pediatrics and co-first author, found that C. elegans with the patient’s genetic variant moved slower than roundworms with a healthy copy of the gene did, revealing that the genetic change can affect mobility and the nervous system.