Researchers at the Icahn School of Medicine at Mount Sinai, and collaborators at the University of Bristol, KU Leuven, and the NIHR BioResource, have identified a neurodevelopmental disorder, caused by mutations in a single gene, that affects tens of thousands of people worldwide. The study, involving genetic analysis of thousands of individuals with intellectual disability (ID), discovered that mutations in a small noncoding gene called RNU4-2 cause a collection of developmental symptoms that had not previously been tied to a distinct genetic disorder. The findings, the researchers say, will improve clinical diagnostic services for patients with neurodevelopmental disorders.

“We performed a large genetic association analysis to identify rare variants in noncoding genes that might be responsible for neurodevelopmental disorders,” commented Daniel Greene, PhD, assistant professor of genetics and genomics sciences at Icahn Mount Sinai. “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.” Greene is first author of the team’s published paper in Nature Medicine, titled, “Mutations in the U4 snRNA gene RNU4-2 cause one of the most prevalent monogenic neurodevelopmental disorders.”

Neurodevelopmental disorders, which often become evident in young children, 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).

Noncoding genes are stretches of DNA that do not produce proteins. More than 99% of genes known to harbor mutations that cause neurodevelopmental disorders encode proteins. And while scientists have, to date, confidently linked 1,427 genes with intellectual disability, most ID cases still remain unexplained following genetic testing, the authors wrote. “All but nine of the 1,427 known genes are protein coding, in part because the largest genetic studies of ID have used whole-exome sequencing (WES), which typically omits noncoding genes.” The researchers hypothesized that noncoding genes might also harbor mutations leading to intellectual disability.

For their reported study the investigators turned to whole-genome sequencing data in the U.K.’s National Genomic Research Library to compare the burden of rare genetic variants in 41,132 noncoding genes between 5,529 unrelated cases with intellectual disability and 46,401 unrelated controls. The results indicated that RNU4-2, which encodes U4 snRNA, a critical component of the spliceosome, was the gene most strongly associated with ID. “We implicated de novo variants among 47 cases in two regions of RNU4-2 in the etiology of a syndrome characterized by ID, microcephaly, short stature, hypotonia, seizures, and motor delay,” the investigators stated. They also replicated their finding in another three data cohorts, taking the number of cases up to 73. “Nineteen of the 26 affected probands acquired the variant de novo, six acquired the variant with inheritance that was unknown due to a lack of parental genotype data, and one case inherited variant n.76C>T from an affected mother.”

The discovery is particularly 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 U.K.’s Genomic Medicine Service. Notably, these mutations are typically spontaneous and not inherited, providing important insights into the nature of the condition.

“Analysis of national genomic diagnostic data showed RNU4-2 to be a more common etiological gene for neurodevelopmental abnormality than any previously reported autosomal gene,” the researchers stated. “Our findings add to growing evidence of spliceosome dysfunction in the etiologies of neurological disorders.”

Schematic showing the structures of U4 and U6 RNAs, and the interactions between them. Mutations in the highlighted regions of U4 cause a neurodevelopmental disorder that affects tens of thousands. [Lab of Ernest Turro, PhD, at Icahn Mount Sinai.]
Schematic showing the structures of U4 and U6 RNAs, and the interactions between them. Mutations in the highlighted regions of U4 cause a neurodevelopmental disorder that affects tens of thousands of patients. [Lab of Ernest Turro, PhD, at Icahn Mount Sinai.]

Senior study author Ernest Turro, PhD, associate professor of genetics and genomic sciences at Icahn Mount Sinai and a visitor at the University of Cambridge, further noted, “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.”

The researchers aim to explore the molecular mechanisms underlying this syndrome experimentally. A deeper understanding could then provide biological insights that might lead to future targeted interventions.

“What I found remarkable is how such a common cause of a neurodevelopmental disorder has been missed in the field because we’ve been focusing on coding genes,” said Heather Mefford, MD, PhD, of the Center for Pediatric Neurological Disease Research at St. Jude Children’s Research Hospital, who was not involved in the research. “This study’s discovery of mutations in noncoding 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 new diagnostic possibilities and research opportunities.”

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