Scientists identify genetic disease that can lead to intellectual disability

A newly identified neurodevelopmental disorder could explain tens of thousands of cases of intellectual disability whose cause was previously unknown, a new study suggests.

The research, published Friday in the journal Nature Medicine, studies the effects of mutations in the RNU4-2 gene, found in all animals, plants and fungi.

The gene plays an important role in gene splicing – the process of cutting out parts of genetic material and putting others together. Ernest Turro, lead author of the new study and associate professor of genetics and genomic sciences at the Icahn School of Medicine at Mount Sinai, said that in theory, mutations in the RNU4-2 gene could disrupt this process of splicing, ultimately leading to an abnormal brain. development and intellectual disability.

This type of disability is characterized by significant limitations in a person’s ability to learn, reason, problem solve, communicate, or socialize, and it is often indicated by a low IQ. According to research, people with this disorder may also have seizures, motor delays, a small head, short stature, or low muscle mass.

Researchers hope that genetic testing for intellectual disability in children can be quickly updated to screen for mutations.

“A considerable number of families will finally be able to benefit from a genetic diagnosis,” Turro said.

Dr. Hakon Hakonarson, director of the Center for Applied Genomics at 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 results could “explain a good number of cases of intellectual disability”. cases that are currently unexplained.

The study estimates that up to 1 in 20,000 young people could suffer from this condition. Researchers do not know the life expectancy associated with this disease and therefore have not estimated its prevalence among older adults, but Turro said some people with the genetic mutation have lived into adulthood.

The estimate suggests that this condition is slightly less common than Rett syndrome, a genetic disorder that causes rapid loss of coordination, speech and mobility in babies and affects about 1 in 10,000 female infants.

But Dr. Jeffrey Gruen, a professor of pediatrics and genetics at the Yale School of Medicine who was not involved in the research, said that mutations in the RNU4-2 gene may turn out to be less common than suggested. study. He also questioned whether all people with mutations would have obvious problems with learning or development.

“There are probably tens of thousands of people around the world who carry it, 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 likely cause at least some symptoms.

“The likelihood of it causing disease with these variants – which are not seen in healthy people by the way – is almost 100%,” he said.

The findings are based on data from the National Genomic Research Library, which contains information on the genomes – the entire genetic code of a person – of people in the UK. The study examined the genomes of more than 77,000 participants.

Historically, studies of neurodevelopmental disorders have focused only on a small part of the genome, in particular the so-called coding genes involved in protein production. Of the 1,427 genes linked to intellectual disability, all but nine are coding genes.

Instead, Turro and his research team looked at noncoding genes — which don’t produce proteins — in about 5,500 people with intellectual disabilities. Mutations in the RNU4-2 gene were strongly associated with this group, compared to around 46,000 people without intellectual disabilities.

“There is no doubt that this article will spark a lot of study,” Hakonarson said. “People will go looking for additional genes, because there are many non-coding RNA genes.”

Mutations in the RNU4-2 gene appear to occur randomly, so they probably cannot be passed from parent to child. For that reason, getting a diagnosis could be a comfort to parents who want to have more children, Turro said.

Researchers said it will take some time before they determine whether the disease can be treated with drugs or gene therapy.

“This is an extremely difficult group of disorders to treat therapeutically,” said Andrew Mumford, study co-author and research director of the NHS South West England Genomic Medicine Service. during a call with reporters.

But even without treatment available, he added, families often benefit from a diagnosis.

“It helps them come to terms with the impact,” he said. “Being able to say to someone, ‘Yes, we found the cause of your child’s developmental disorder,’ is incredibly powerful.”

Gruen said the discovery could also help connect families whose children have the same genetic disorder so they can share stories and offer support.

“You might get a sense of what the future holds for them,” Gruen said. “Is this something that could be fixed?” Can we expect there to be language? Can we expect engine problems? This is also very, very important to know.