A genetic disorder that causes severe disabilities in children and adults has been discovered by researchers who believe the newly identified condition could affect hundreds of thousands of people around the world.
Scientists have already diagnosed hundreds of people in the UK, Europe and the US after examining their DNA and noticing mutations in the gene linked to the disorder. It is expected that many more will be found as further testing takes place.
The condition causes severe developmental delay and many of those diagnosed are unable to speak, are fed through a tube and suffer seizures. The disorder produces characteristic facial features, such as large cupped ears, full cheeks and a mouth with downward angles.
“It’s not unusual to discover a neurodevelopmental disorder, but it’s incredibly unusual to discover one that’s so common,” said Nicola Whiffin, an associate professor at the Big Data Institute and Center for Human Genetics at the University of Oxford. “It’s surprisingly frequent. There are a lot of questions about why we haven’t seen this before.”
About 60% of people with a neurodevelopmental disorder (NDD) remain undiagnosed after extensive genetic testing, leaving them in the dark about the underlying cause.
A formal diagnosis can help patients and families by identifying the cause of the condition and connecting them with others to form support groups. For scientists, knowing the genetics of an NDD paves the way for broader testing and research into future therapies.
Most 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 the patients, all enrolled 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 account for nearly 0.5% of all neurodevelopmental disorders worldwide, a small portion but one that amounts to hundreds of thousands of people. Details are published in Nature.
“We know about hundreds of patients, but one of the key issues is that we are limited to making diagnoses in patients where we have their whole genome,” Whiffin said. Decoding patients’ entire genetic code is becoming common in the UK and other developed countries, but some nations lack the means to read entire genomes at scale.
One hope for the future is to use artificial intelligence tools to recognize the disorder from facial features alone. If it pans out, doctors could diagnose patients with the disease simply by uploading their portrait for analysis.
Three years ago, Nicole Cedor, the mother of 10-year-old Mia Joy, was told there was nothing more doctors could do to identify her daughter’s condition. She was recently diagnosed with the disorder.
“We resigned ourselves to the fact that we might never find out. So, you can imagine our shock to get this news,” she said. “We are so grateful to every person on the research teams who worked tirelessly to find this diagnosis. It’s one thing to write papers and crunch all that data, then another to see a family with a precious unique child living it out day by day. This is where the data meets real life. We like to refer to RNU4-2 as “renewed” as our family is renewed by this new information and hope for the future.
Whiffin said there are several benefits to having a diagnosis. Some mothers fear that they may have caused the disorder by doing something wrong during pregnancy, putting the diagnosis to bed. 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 very exciting point where we have all these genome-targeted therapies,” she said. “There is a question of whether we can make a big difference to something that is so developmental, but maybe we can do something to improve the attacks, to improve quality of life. At least it opens the door to try 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 disease after Whiffin shared details of the discovery. “As we reached out to other collaborating researchers, they also identified an unprecedented number of diagnoses, including from many patients and families who have long sought answers,” she said.
“Not having a diagnosis or an explanation for why the medical problems occur leaves patients and their families without a community, not knowing what other complications may come, and unable to know what steps to take next. not to take.”
O’Donnell-Luria said identifying the RNU4-2 diagnosis was an important first step toward a better understanding of the underlying biology of the condition, and provides hope and a potential research path toward a therapy .
