De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome 2024 Chen et al

Abstract

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes1. Large genome-sequenced cohorts are improving our ability to discover new diagnoses in the non-coding genome. Here, we identify the non-coding RNA RNU4-2 as a syndromic NDD gene. RNU4-2 encodes the U4 small nuclear RNA (snRNA), which is a critical component of the U4/U6.U5 tri-snRNP complex of the major spliceosome2.

We identify an 18 bp region of RNU4-2 mapping to two structural elements in the U4/U6 snRNA duplex (the T-loop and Stem III) that is severely depleted of variation in the general population, but in which we identify heterozygous variants in 115 individuals with NDD. Most individuals (77.4%) have the same highly recurrent single base insertion (n.64_65insT). In 54 individuals where it could be determined, the de novo variants were all on the maternal allele.

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. Finally, we estimate that variants in this 18 bp region explain 0.4% of individuals with NDD. This work underscores the importance of non-coding genes in rare disorders and will provide a diagnosis to thousands of individuals with NDD worldwide.

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

 

Scientists uncover genetic disorder that may affect thousands around world

"A genetic disorder that causes severe disabilities in children and adults has been discovered by researchers who believe the newly identified condition could affect hundreds of thousands of people around the world.

Scientists have already diagnosed hundreds of people in the UK, Europe and the US after examining their DNA and spotting mutations in the gene linked to the disorder. Far more are expected to be found as further testing takes place.

The condition causes severe developmental delay and many of those diagnosed are unable to speak, are fed through a tube and have seizures. The disorder produces characteristic facial features, such as large cupped ears, full cheeks and a mouth with downturned corners.

“It’s not unusual to discover a neurodevelopmental disorder, but it is incredibly unusual to discover one that is this common,” said Nicola Whiffin, an associate professor at the Big Data Institute and Centre for Human Genetics at the University of Oxford. “This is surprisingly frequent. There are a lot of questions as to why we haven’t seen this before.”"

https://www.theguardian.com/science...sorder-that-may-affect-thousands-around-world

 

"A formal diagnosis can help patients and families by identifying the reason for the condition and connecting them with others to form support groups. For scientists, knowing the genetics of an NDD paves the way for broader testing and research on future therapies."