Mutations in the U4 snRNA gene RNU4-2 cause one of the most prevalent monogenic neurodevelopmental disorders

• Published in: Nature medicine Vol. 30; no. 8; pp. 2165 - 2169
• Main Authors: Greene, Daniel, Thys, Chantal, Berry, Ian R., Jarvis, Joanna, Ortibus, Els, Mumford, Andrew D., Freson, Kathleen, Turro, Ernest
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.08.2024; Nature Publishing Group
• Subjects: 631/208/2489/144; 631/208/366; Association analysis; Biomedical and Life Sciences; Biomedicine; Brief Communication; Cancer Research; Critical components; Etiology; Genetic analysis; Genetic screening; Genomic analysis; Hypotonia; Infectious Diseases; Intellectual disabilities; Metabolic Diseases; Microencephaly; Molecular Medicine; Mutation; Neurodevelopmental disorders; Neurological diseases; Neurosciences; Seizures; snRNA
• ISSN: 1078-8956; 1546-170X; 1546-170X
• DOI: 10.1038/s41591-024-03085-5

Most people with intellectual disability (ID) do not receive a molecular diagnosis following genetic testing. To identify new etiologies of ID, we performed a genetic association analysis comparing the burden of rare variants in 41,132 noncoding genes between 5,529 unrelated cases and 46,401 unrelated controls. RNU4-2 , which encodes U4 small nuclear RNA, a critical component of the spliceosome, was the most strongly associated gene. 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. We replicated this finding in three collections, bringing the number of unrelated cases to 73. 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. Our findings add to the growing evidence of spliceosome dysfunction in the etiologies of neurological disorders. Mutations in a small noncoding gene called RNU4-2 are responsible for one of the most common neurodevelopmental disorders that is mediated by a single gene.