Genetic Cause of An Intellectual Disability Identified in RNU4-2 Gene

New study links genetic changes in a non-coding gene called RNU4-2 to neurodevelopmental disorders

Author: Icahn School of Medicine at Mount Sinai
Published: 2024/06/02
Post type: Research, Study, Analysis – Peer Reviewed: Yeah
Content: SummaryIntroductionMajor – Related

Synopsis: Researchers have discovered a neurodevelopmental disorder linked to mutations in a single gene (RNU4-2), affecting tens of thousands of people worldwide. Through rigorous genetic analysis, researchers discovered that mutations in a small noncoding gene called RNU4-2 cause a range of developmental symptoms that have not previously been linked to a distinct genetic disorder. More than 99 percent 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.

Introduction

Researchers at the Icahn School of Medicine at Mount Sinai and others have identified a neurodevelopmental disorder, caused by mutations in a single gene, that affects tens of thousands of people worldwide. The work, published in the May 31, 2024 online edition of Nature medicine, was conducted in collaboration with colleagues at the University of Bristol, United Kingdom; KU Leuven, Belgium; and the NIHR BioResource, currently based at the University of Cambridge, UK. The findings will improve clinical diagnostic services for patients with neurodevelopmental disorders.

Main summary

Through rigorous genetic analysis, researchers discovered that mutations in a small noncoding gene called RNU4-2 cause a range of developmental symptoms that have not previously been linked to a distinct genetic disorder. Non-coding genes are parts of DNA that do not make proteins. The researchers used whole genome sequencing data at 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 of intellectual disability and 46,401 unrelated controls.

Continues below image.

Scheme 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. Image credit: Laboratory of Ernest Turro, PhD, at Icahn Mount Sinai.

Continued…

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 Genomic Medicine Service. Notably, these mutations are often spontaneous and non-inherited, providing important information about the nature of the condition.

“We performed a large genetic association analysis to identify rare variants in non-coding genes that could be responsible for neurodevelopmental disorders,” says the study’s first author, Daniel Greene, PhD, assistant professor of genetics and genomic sciences at Icahn Mount Sinai. and visitor. at the University of Cambridge. “Today, finding a single gene harboring genetic variants responsible for tens of thousands of patients with a rare disease is exceptionally rare. Our discovery eluded researchers for years due to various analytical and sequencing challenges.”

More than 99 percent 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 (e.g., learning, reasoning, problem solving) and adaptive behavior (e.g., social and practical skills).

“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,” says senior study author Ernest Turro, PhD, associate professor of genetics and genomic sciences at Icahn Mount Sinai and visiting University of Cambridge. “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 relatives, ending many diagnostic odysseys. “

Next, the researchers plan to experimentally explore the molecular mechanisms underlying this syndrome. This deeper understanding aims to provide biological insights that could one day lead to targeted interventions.

“What I found surprising is how such a common cause of a neurodevelopmental disorder has been overlooked in the field because we have focused on gene coding,” says Heather Mefford, MD, PhD, of the Center for Disease Research. Pediatric Neurology Department 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 an important 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.”

About the newspaper

The document is titled “Mutations in the U4 snRNA RNU4-2 gene cause one of the most prevalent monogenic neurodevelopmental disorders.”

Authors

The remaining authors of the paper are Chantal Thys (KU Leuven, Belgium); Ian R. Berry, MD (University of Bristol, United Kingdom); Joanna Jarvis, MD (Birmingham Women’s Hospital, United Kingdom); Els Ortibus, MD, PhD (KU Leuven, Belgium); Andrew D. Mumford, MD (University of Bristol, UK); and Kathleen Freson, PhD (KU Leuven, Belgium).

Money

The work was supported, in part, by NIH awards R01HL161365 and R03HD111492. Please see the document for more details on funding.

Icahn School of Medicine at Mount Sinai

The Icahn School of Medicine at Mount Sinai, located in New York City on the border of the Upper East Side and East Harlem, is internationally recognized for its outstanding research, education and clinical care programs. It is the only academic partner of the eight member hospitals* of the Mount Sinai Health System, one of the largest academic health systems in the United States, providing care to a large and diverse patient population.

*Mount Sinai Health System member hospitals: Mount Sinai Hospital; Mount Sinai Bet Israel; Mount Sinai Brooklyn; Mount Sinai Morningside; Queens of Mount Sinai; Mount Sinai South Nassau; Mount Sinai West; and New York Eye and Ear Infirmary at Mount Sinai.

Attribution/Source(s):

This peer-reviewed publication titled Genetic cause of an intellectual disability identified in the RNU4-2 gene was selected for publication by the editors of Disabled World due to its relevance to the disability community. While content may have been edited for style, clarity, or brevity, it was originally written by Icahn School of Medicine at Mount Sinai and published on 06/02/2024. For more details or clarifications, you can contact Icahn School of Medicine at Mount Sinai directly on mountsinai.org Disabled World does not provide any warranty or endorsement related to this article.

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Cite this page (APA): Icahn School of Medicine at Mount Sinai. (2024, June 2). Genetic cause of an intellectual disability identified in the RNU4-2 gene. Disabled world. Retrieved June 2, 2024 from www.disabled-world.com/disability/types/cognitive/rnu4-2.php

Permanent link: Genetic cause of an intellectual disability identified in the RNU4-2 gene: Researchers have discovered a neurodevelopmental disorder linked to mutations in a single gene (RNU4-2), affecting tens of thousands of people worldwide.

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