De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome
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 R...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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Nature Research
2024
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| _version_ | 1811140521930784768 |
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| author | Chen, Y Dawes, R Kim, HC Ljungdahl, A Stenton, SL Walker, S Lord, J Lemire, G Martin-Geary, AC Ganesh, VS Ma, J Ellingford, JM Delage, E D’Souza, EN Dong, S Adams, DR Allan, K Bakshi, M Baldwin, EE Berger, SI Bernstein, JA Bhatnagar, I Blair, E Brown, NJ Goriely, A Hinch, AG Stewart, HS Fica, SM Sanders, SJ Whiffin, N |
| author_facet | Chen, Y Dawes, R Kim, HC Ljungdahl, A Stenton, SL Walker, S Lord, J Lemire, G Martin-Geary, AC Ganesh, VS Ma, J Ellingford, JM Delage, E D’Souza, EN Dong, S Adams, DR Allan, K Bakshi, M Baldwin, EE Berger, SI Bernstein, JA Bhatnagar, I Blair, E Brown, NJ Goriely, A Hinch, AG Stewart, HS Fica, SM Sanders, SJ Whiffin, N |
| author_sort | Chen, Y |
| collection | OXFORD |
| description | 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 base pair 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 in whom 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 homologues. Using RNA sequencing, we show how 5′ splice-site use 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 base pair 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. |
| first_indexed | 2024-09-25T04:23:19Z |
| format | Journal article |
| id | oxford-uuid:38bfc81b-085d-4113-9d4d-cec9ba835dcd |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-09-25T04:23:19Z |
| publishDate | 2024 |
| publisher | Nature Research |
| record_format | dspace |
| spelling | oxford-uuid:38bfc81b-085d-4113-9d4d-cec9ba835dcd2024-08-21T20:15:57ZDe novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndromeJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:38bfc81b-085d-4113-9d4d-cec9ba835dcdEnglishJisc Publications RouterNature Research2024Chen, YDawes, RKim, HCLjungdahl, AStenton, SLWalker, SLord, JLemire, GMartin-Geary, ACGanesh, VSMa, JEllingford, JMDelage, ED’Souza, ENDong, SAdams, DRAllan, KBakshi, MBaldwin, EEBerger, SIBernstein, JABhatnagar, IBlair, EBrown, NJGoriely, AHinch, AGStewart, HSFica, SMSanders, SJWhiffin, NAround 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 base pair 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 in whom 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 homologues. Using RNA sequencing, we show how 5′ splice-site use 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 base pair 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. |
| spellingShingle | Chen, Y Dawes, R Kim, HC Ljungdahl, A Stenton, SL Walker, S Lord, J Lemire, G Martin-Geary, AC Ganesh, VS Ma, J Ellingford, JM Delage, E D’Souza, EN Dong, S Adams, DR Allan, K Bakshi, M Baldwin, EE Berger, SI Bernstein, JA Bhatnagar, I Blair, E Brown, NJ Goriely, A Hinch, AG Stewart, HS Fica, SM Sanders, SJ Whiffin, N De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome |
| title | De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome |
| title_full | De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome |
| title_fullStr | De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome |
| title_full_unstemmed | De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome |
| title_short | De novo variants in the RNU4-2 snRNA cause a frequent neurodevelopmental syndrome |
| title_sort | de novo variants in the rnu4 2 snrna cause a frequent neurodevelopmental syndrome |
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