Frequent Neurodevelopmental Syndrome Caused by De Novo Variants in the RNU4-2 snRNA Gene

Core Concepts

Heterozygous variants in a highly conserved 18 bp region of the RNU4-2 snRNA gene, primarily a recurrent single base insertion, cause a frequent neurodevelopmental syndrome.

Abstract

The article reports the discovery of a new genetic cause of neurodevelopmental disorders (NDDs). Around 60% of individuals with NDDs remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes. The researchers identified the non-coding RNA gene RNU4-2, which encodes the U4 small nuclear RNA (snRNA), as a syndromic NDD gene.

The key findings are:

• An 18 bp region of RNU4-2 mapping to structural elements in the U4/U6 snRNA duplex is severely depleted of variation in the general population, but heterozygous variants in this region were identified in 115 individuals with NDDs.
• The most common variant is a recurrent single base insertion (n.64_65insT), found in 77.4% of the individuals.
• In the 54 individuals where parental origin could be determined, all de novo variants were on the maternal allele.
• RNU4-2 is highly expressed in the developing human brain, in contrast to the other U4 homologs.
• RNA-sequencing analysis showed that 5' splice site usage is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation.
• Variants in this 18 bp region of RNU4-2 are estimated to explain 0.4% of individuals with NDDs.

The work highlights the importance of non-coding genes in rare disorders and provides a new genetic diagnosis for thousands of individuals with NDDs worldwide.

Stats

Around 60% of individuals with neurodevelopmental disorders remain undiagnosed after comprehensive genetic testing.
Heterozygous variants in a highly conserved 18 bp region of the RNU4-2 snRNA gene were identified in 115 individuals with neurodevelopmental disorders.
The most common variant is a recurrent single base insertion (n.64_65insT), found in 77.4% of the individuals.
In the 54 individuals where parental origin could be determined, all de novo variants were on the maternal allele.
Variants in this 18 bp region of RNU4-2 are estimated to explain 0.4% of individuals with neurodevelopmental disorders.

Quotes

"Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1."
"We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to RNU4-1 and other U4 homologs."
"Using RNA-sequencing, we show how 5' splice site usage is systematically disrupted in individuals with RNU4-2 variants, consistent with the known role of this region during spliceosome activation."

Key Insights Distilled From

De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome - Nature

by Yuyang Chen,... at www.nature.com 07-11-2024

https://www.nature.com/articles/s41586-024-07773-7

Deeper Inquiries

What are the potential mechanisms by which the identified RNU4-2 variants lead to the observed neurodevelopmental phenotypes?

The identified RNU4-2 variants are implicated in causing neurodevelopmental phenotypes through their disruption of the U4 small nuclear RNA (snRNA) function within the U4/U6.U5 tri-snRNP complex of the major spliceosome. The 18 bp region of RNU4-2, where these variants are located, corresponds to critical structural elements in the U4/U6 snRNA duplex, specifically the T-loop and Stem III. Variants in this region, such as the highly recurrent single base insertion (n.64_65insT), lead to aberrant splicing patterns by affecting spliceosome activation. This disruption in 5’ splice site usage, as demonstrated by RNA-sequencing, can result in the misregulation of gene expression during crucial developmental processes in the brain. Therefore, the RNU4-2 variants likely contribute to neurodevelopmental disorders by perturbing the splicing machinery and subsequently impacting the expression of genes essential for proper brain development.

How do the RNU4-2 variants compare to other known genetic causes of neurodevelopmental disorders in terms of clinical presentation and severity?

In comparison to other known genetic causes of neurodevelopmental disorders, the RNU4-2 variants represent a unique class of pathogenic variants that affect a non-coding RNA gene. While protein-coding genes have traditionally been the focus of genetic testing for NDD, the discovery of RNU4-2 as a syndromic NDD gene highlights the importance of non-coding elements in disease etiology. The highly recurrent nature of the RNU4-2 variant (n.64_65insT) and its maternal inheritance pattern in affected individuals distinguish it from many other genetic causes of NDD. Additionally, the specific impact of RNU4-2 variants on spliceosome function and splicing dysregulation sets them apart in terms of the underlying molecular mechanism driving neurodevelopmental phenotypes. The clinical presentation and severity of NDD associated with RNU4-2 variants may exhibit variability but are characterized by disruptions in neurodevelopmental processes linked to splicing defects, emphasizing the distinctiveness of this genetic etiology.

Could the insights from this study on the role of non-coding RNAs in neurodevelopment lead to the discovery of additional non-coding genetic contributors to other complex diseases?

The insights gained from the identification of RNU4-2 as a causative gene for neurodevelopmental disorders underscore the potential for discovering additional non-coding genetic contributors to a wide range of complex diseases. The study highlights the critical role of non-coding RNAs, such as RNU4-2, in regulating essential cellular processes and their implication in disease pathogenesis. By demonstrating the impact of non-coding variants on splicing regulation and neurodevelopment, this research sets a precedent for exploring the involvement of non-coding elements in other complex diseases beyond NDD. The systematic disruption of splice site usage observed in individuals with RNU4-2 variants suggests a broader relevance of non-coding RNAs in modulating gene expression and cellular functions. Therefore, the findings from this study could pave the way for uncovering additional non-coding genetic contributors to diverse complex diseases, offering new insights into disease mechanisms and potential therapeutic targets.