A newly identified neurodevelopmental disorder may explain tens of thousands of cases of intellectual disability whose cause was previously unknown, according to a new study.
The research, published Friday in the journal Nature Medicine, investigates the effects of mutations in the RNU4-2 gene, which is found in all animals, plants and fungi.
The gene plays an important role in gene splicing – the process of cutting out pieces of genetic material and splicing others together. Ernest Turro, senior author of the new study and an associate professor of genetics and genomic science at the Icahn School of Medicine at Mount Sinai, said that in theory, mutations in the RNU4-2 gene could disrupt the binding process, eventually leading to in the abnormal brain. development and intellectual disability.
This type of disability is characterized by significant limitations in a person’s ability to learn, reason, solve problems, communicate or socialize, and is often indicated by a low IQ. People with the disorder may also have seizures, motor delays, small heads, short stature or low muscle mass, according to research.
Researchers hope genetic tests for intellectual disabilities in children can soon be updated to screen for mutations.
“A significant number of families will finally be able to have a genetic diagnosis,” Turro said.
Dr. Hakon Hakonarson, director of the Center for Applied Genomics at the Children’s Hospital of Philadelphia, who was not involved in the study, said that because most cases of intellectual disability have no known cause, the findings could “explain a a good number of cases are currently unexplained.”
The study estimates that up to 1 in 20,000 young people may have the condition. Researchers don’t know about the lifespan associated with the disorder, so they haven’t estimated its prevalence in older adults, but Turro said some people with the genetic mutation have lived into adulthood.
The estimate suggests the condition is slightly less common than Rett syndrome, a genetic disorder that causes babies to rapidly lose coordination, speech and mobility and affects about 1 in 10,000 female babies.
But Dr. Jeffrey Gruen, a professor of pediatrics and genetics at Yale School of Medicine, who was not part of the research, said mutations in the RNU4-2 gene may turn out to be less common than the study suggests. He also questioned whether everyone with mutations would have obvious learning or developmental problems.
“There are probably tens of thousands of people around the world who carry this, but does it cause intellectual disability in those tens of thousands? I don’t know,” he said. Gruen added, however, that the discovery is important.
Hakonarson said the mutations probably cause at least some symptoms.
“The chance that this is disease-causing with these variants — which are not seen, by the way, in healthy people — is almost 100%,” he said.
The findings are based on data from the National Genomic Research Library, which contains information about the genomes – the entirety of a person’s genetic code – of people in the UK. The study examined the genomes of more than 77,000 participants.
Historically, studies of neurodevelopmental disorders have looked at only a small part of the genome—specifically, so-called coding genes that are involved in protein production. Of the 1,427 genes associated with intellectual disability, all but nine are coding genes.
Instead, Turro and his research team looked at non-coding genes — which don’t make proteins — in about 5,500 people with intellectual disabilities. Mutations in the RNU4-2 gene were strongly associated with that group, compared with about 46,000 people who did not have an intellectual disability.
“There is no doubt that this paper will provoke a lot of study now,” Hakonarson said. “People will go hunting for additional genes because there are so many non-coding RNA genes.”
Mutations in the RNU4-2 gene appear to occur randomly, so they most likely cannot be passed from parent to child. For this reason, receiving a diagnosis can be a comfort to parents who want to have more children, Turro said.
Researchers said it will take some time before they know whether the disorder can be treated with drugs or gene therapy.
“These are an extremely difficult group of disorders to treat therapeutically,” said Andrew Mumford, a study co-author and research director of the NHS South West England Genomic Medicine Service, in a call with reporters.
But even without an available treatment, he added, families often benefit from a diagnosis.
“It helps them come to terms with the impact,” he said. “Being able to tell someone, ‘Yes, we’ve found the cause of your child’s developmental disorder’ is extremely powerful.”
Gruen said the discovery could also help connect families whose children have the same genetic condition so they can share stories and offer support.
“You can get an idea of what the future holds for them,” Gruen said. “Is this something that can be corrected? Can we expect it to have language? Can we expect motor problems? This is also very, very important to know.”
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