Through rigorous genetic analysis, the researchers discovered that mutations in a small non-coding gene called RNU4-2 cause a collection of developmental symptoms that had not previously been tied to a distinct genetic disorder. Non-coding genes are parts of DNA that do not produce proteins. The investigators used whole-genome sequencing data in the UK's National Genomic Research Library to compare the burden of rare genetic variants in 41,132 non-coding genes between 5,529 unrelated cases with intellectual disability and 46,401 unrelated controls.
The discovery is significant, 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's Genomic Medicine Service. Notably, these mutations are typically spontaneous and not inherited, providing important insights into the nature of the condition.
Daniel Greene, PhD, Assistant Professor of Genetics and Genomics Sciences at Icahn Mount Sinai and a Visitor at the University of Cambridge, and the study's first author, said: “We performed a large genetic association analysis to identify rare variants in non-coding genes that might be responsible for neurodevelopmental disorders. Nowadays, finding a single gene that harbors genetic variants responsible for tens of thousands of patients with a rare disease is exceptionally unusual. Our discovery eluded researchers for years due to various sequencing and analytical challenges.”
More than 99 percent of genes known to harbor mutations that cause neurodevelopmental disorders encode proteins. The researchers hypothesized that non-coding genes, which don't produce proteins, could also host mutations leading to intellectual disability. Neurodevelopmental disorders, which often appear before grade school, involve developmental deficits affecting personal, social, academic, or occupational functioning. Intellectual disability specifically includes significant limitations in intellectual functioning (e.g., learning, reasoning, problem-solving) and adaptive behavior (e.g., social and practical skills).
Ernest Turro, PhD, Associate Professor of Genetics and Genomic Sciences at Icahn Mount Sinai and a Visitor at the University of Cambridge, and the study's senior author explains “The genetic changes we found affect a very short gene, only 141 units long, but this gene plays a crucial role in a basic biological function of cells, called gene splicing, which is present in all animals, plants and fungi.
“Most people with a neurodevelopmental disorder do not receive a molecular diagnosis following genetic testing. Thanks to this study, tens of thousands of families will now be able to obtain a molecular diagnosis for their affected family members, bringing many diagnostic odysseys to a close.”
Andrew Mumford, Professor of Haematology at the University of Bristol and one of the study's lead authors, said: “I am delighted to have contributed to this extraordinary gene discovery and now look forward to ensuring translation as an essential diagnostic tool for neurodevelopmental disorders within the NHS Genomic Medicine Service."
Next, the researchers plan to explore the molecular mechanisms underlying this syndrome experimentally. This deeper understanding aims to provide biological insights that could one day lead to targeted interventions.
The work was supported, in part, by National Institute of Health (NIH) awards.
Paper
'Mutations in the U4 snRNA gene RNU4-2 cause one of the most prevalent monogenic neurodevelopmental disorders' by Daniel Greene et al. in Nature Medicine