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

Daniel Greene, Chantal Thys, Ian R Berry, Joanna Jarvis, Els Ortibus, Andrew D Mumford, Kathleen Freson, Ernest Turro*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

6 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)2165-2169
Number of pages5
JournalNature Medicine
Volume30
Issue number8
Early online date31 May 2024
DOIs
Publication statusE-pub ahead of print - 31 May 2024

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

Fingerprint

Dive into the research topics of 'Mutations in the U4 snRNA gene RNU4-2 cause one of the most prevalent monogenic neurodevelopmental disorders'. Together they form a unique fingerprint.

Cite this