Researchers have discovered a genetic disorder that causes severe disabilities in children and adults, and believe the newly discovered condition could affect hundreds of thousands of people worldwide.
Scientists have already diagnosed hundreds of people in the UK, Europe and the US after examining their DNA and discovering mutations in the gene linked to the disorder. Many more are expected to be found as more tests are carried out.
The condition causes severe developmental delay and many of those diagnosed are unable to speak, are tube-fed and have seizures. The condition produces characteristic facial features such as large, cupped ears, full cheeks and a mouth with downward corners.
“It’s not unusual to find a neurodevelopmental disorder, but it’s incredibly unusual to find one that’s so common,” said Nicola Whiffin, a senior lecturer at the Big Data Institute and Centre for Human Genetics at the University of Oxford. “This is surprisingly common. There are a lot of questions about why we didn’t see this before.”
About 60% of people with a neurodevelopmental disorder (NDD) remain undetected, even after extensive genetic testing, leaving them in the dark about the underlying cause.
A formal diagnosis can help patients and families by identifying the reason for the condition and connecting them with others to form support groups. For scientists, understanding the genetics of NDD paves the way for broader testing and research into future therapies.
Most of the work aimed at discovering the genetic causes of NDDs focuses on genes that the body uses to make proteins, the building blocks of life. But after analyzing the complete genomes of nearly 9,000 people with undiagnosed NDDs, an international collaboration led by Whiffin made a serendipitous discovery.
Dozens of patients, all taking part in the 100,000 Genomes Project, led by Genomics England and NHS England, had mutations in the same gene, RNU4-2, which is not used to make proteins.
Mutations in the gene are estimated to be responsible for nearly 0.5% of all neurodevelopmental disorders worldwide, a small percentage but one that amounts to hundreds of thousands of people. Details are published in Nature.
“We know of hundreds of patients, but one of the major problems is that we are limited to diagnosing patients for whom we have the entire genome,” Whiffin said. Decoding the entire genetic code of patients is becoming increasingly common in the UK and other developed countries, but some countries lack the resources to read the entire genome on a large scale.
One hope for the future is to use artificial intelligence tools to recognize the disorder based on facial features alone. If successful, doctors could diagnose patients with the disorder simply by uploading their portrait for analysis.
Three years ago, Nicole Cedor, mother of 10-year-old Mia Joy, was told that there was nothing doctors could do to identify her daughter’s condition. She was recently diagnosed.
“We’ve come to terms with the fact that we may never know. So you can imagine how shocked we were when we got this news,” she said. “We are so grateful to everyone on the research teams who worked tirelessly to find this diagnosis. It’s one thing to write papers and process all that data, but it’s another thing to see a family with a precious, unique child who lives it day in and day out. This is where the data meets real life. We like to call RNU4-2 ‘renew,’ because our family is renewed by this new information and hope for the future.”
Whiffin said there are several benefits to a diagnosis. Some mothers fear that they caused the disorder by doing something wrong during pregnancy, which makes the diagnosis unnecessary. Perhaps the most important benefit is that affected families can come together and form groups to advocate for further research and support.
There was also hope for the future, Whiffin said. “We’re at a really exciting point where we have all these genome-targeted therapies,” she said. “There’s some question about whether we can make much difference in something that’s so developmentally focused, but maybe we can do something to improve seizures, to improve quality of life. This certainly opens the door to trying those things.”
Dr. Anne O’Donell-Luria, co-director of the Center for Mendelian Genomics at the Broad Institute of MIT and Harvard, identified more than 10 families affected by the disorder after Whiffin shared details of the discovery. “When we reached out to other collaborating researchers, they also identified an unprecedented number of diagnoses, including many patients and families who have been searching for answers for a long time,” she said.
“When there is no diagnosis or explanation for the medical problems, patients and their families are left without a community, without knowing what other complications may arise, and without knowing what steps to take next.”
According to O’Donnell-Luria, identifying the RNU4-2 diagnosis is an important first step toward better understanding the underlying biology of the condition. It offers hope and a possible avenue of research toward a therapy.