They discover that a neurodevelopmental disorder that affects tens of thousands of people and causes intellectual disability is due to mutations in a certain gene, a finding that will improve the diagnosis and treatment of these patients.
Researchers at the Icahn School of Medicine at Mount Sinai and other centers have identified a neurodevelopmental disorder caused by mutations in a single gene, affecting tens of thousands of people worldwide. The findings have been published in Nature Medicine and will improve clinical diagnostic services for patients with neurodevelopmental disorders.
The study was carried out in collaboration with colleagues from the University of Bristol, in the United Kingdom; KU Leuven, Belgium; and the NIHR BioResource, currently based at the University of Cambridge, UK. These findings will improve clinical diagnostic services for patients with neurodevelopmental disorders.
The researchers carried out a rigorous genetic analysis that allowed them to discover that mutations in a small non-coding gene called RNU4-2 cause a series of developmental alterations that had not previously been associated with a specific genetic disorder. Non-coding genes are parts of DNA that do not make proteins.
These scientists used whole genome sequencing data from the UK’s National Genome Research Library to compare the burden of rare genetic variants in 41,132 non-coding genes between 5,529 unrelated cases of intellectual disability and 46,401 unrelated controls.
Its discovery is important as it represents one of the most common single-gene genetic causes of such disorders, ranking second only to Rett syndrome among patients sequenced by the UK Genomic Medicine Service. It should be noted that these mutations are usually spontaneous and not inherited, so the findings provide relevant insights into the nature of the condition.
Neurodevelopmental disorders associated with intellectual disability
“We performed extensive genetic association analysis to identify rare variants in non-coding genes that could be responsible for neurodevelopmental disorders,” said Daniel Greene, Assistant Professor of Genetic and Genomic Sciences at Icahn Mount Sinai and Visiting Fellow at the University of Cambridge. and first author of the study. “Today, finding a single gene containing genetic variants responsible for tens of thousands of patients with a rare disease is exceptionally unusual. Our discovery eluded researchers for years due to several sequencing and analysis challenges.”
More than 99% of the genes known to harbor mutations that cause neurodevelopmental disorders encode proteins. The researchers hypothesized that non-coding genes, which do not produce proteins, could also harbor mutations that lead to intellectual disability.
Neurodevelopmental disorders, which often appear before elementary school, involve developmental deficits that affect personal, social, academic, or occupational functioning. Intellectual disability specifically includes significant limitations in intellectual functioning, for example, learning, reasoning, problem solving, as well as in adaptive behavior, such as, for example, social and practical skills.
“The genetic changes we found affect a very short gene, only 141 units long, but this gene plays a key role in a basic biological function of cells, called gene splicing, which is present in all animals, plants and fungi,” explained Ernest Turro, Associate Professor of Genetic and Genomic Sciences at Icahn Mount Sinai and Visiting Professor at the University of Cambridge, and lead author of the study.
Neurodevelopmental disorders, which often appear before elementary school, involve developmental deficits that affect personal, social, academic, or occupational functioning.
“The majority of people with a neurodevelopmental disorder do not receive a molecular diagnosis after genetic testing. Thanks to this study, tens of thousands of families will now be able to obtain a molecular diagnosis for their affected members, ending many diagnostic odysseys” . The researchers’ next goal is to experimentally explore the molecular mechanisms underlying this syndrome. This deeper understanding aims to provide biological insights that could lead to targeted interventions in the future.
“What I found remarkable is how such a common cause of a neurodevelopmental disorder has been overlooked in the field because we’ve focused on the coding genes,” says Dr. Heather Mefford of the Pediatric Neurological Diseases Research Center. at St. Jude Children’s Research Hospital, which was not involved in the research. “This study’s discovery of mutations in non-coding genes, especially RNU4-2, highlights a significant and previously overlooked cause. It underscores the need to look beyond coding regions, which could reveal many other genetic causes, opening up new diagnostic possibilities and research opportunities”
