{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRecent large‐scale genetic studies have revealed that RNU4-2, which encodes the U4 small nuclear RNA—a crucial component of the spliceosome—is essential for proper pre-mRNA splicing and normal neurodevelopment. Disruption of RNU4-2 function through de novo variants has been implicated in a syndrome marked by intellectual disability, microcephaly, short stature, hypotonia, seizures, and motor delay, highlighting its key role in neuronal development and function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFurther investigation of RNU4-2 has identified an 18-base pair region within its sequence—encompassing structural elements of the U4/U6 snRNA duplex—that is highly conserved in the general population. Notably, recurrent heterozygous variants, including a common single base insertion, disrupt 5′ splice-site usage during spliceosome activation. This disruption correlates with neurodevelopmental disorders and is supported by findings that RNU4-2 is markedly expressed in the developing human brain compared to its homologues. Overall, these alterations in RNU4-2 significantly compromise the efficiency of splicing processes and explain a measurable fraction of neurodevelopmental disorder cases."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Daniel Greene, Chantal Thys, Ian R Berry, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Mutations in the U4 snRNA gene RNU4-2 cause one of the most prevalent monogenic neurodevelopmental disorders."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nat Med (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41591-024-03085-5"}], "href": "https://doi.org/10.1038/s41591-024-03085-5"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38821540"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38821540"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Yuyang Chen, Ruebena Dawes, Hyung Chul Kim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Nature (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1038/s41586-024-07773-7"}], "href": "https://doi.org/10.1038/s41586-024-07773-7"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38991538"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38991538"}]}]}]}