De novo variants in the non-coding spliceosomal snRNA gene 
        RNU4-2 are a frequent cause of syndromic neurodevelopmental disorders.

Yuyang Chen; Ruebena Dawes; Hyung Chul Kim; Sarah L Stenton; Susan Walker; Alicia Ljungdahl; Jenny Lord; Vijay S Ganesh; Jialan Ma; Alexandra C Martin-Geary; Gabrielle Lemire; Elston N D'Souza; Shan Dong; Jamie M Ellingford; David R Adams; Kirsten Allan; Madhura Bakshi; Erin E Baldwin; Seth I Berger; Jonathan A Bernstein; Natasha J Brown; Lindsay C Burrage; Kimberly Chapman; Alison G Compton; Chloe A Cunningham; Precilla D'Souza; Emmanuèle C Délot; Kerith-Rae Dias; Ellen R Elias; Carey-Anne Evans; Lisa Ewans; Kimberly Ezell; Jamie L Fraser; Lyndon Gallacher; Casie A Genetti; Christina L Grant; Tobias Haack; Alma Kuechler; Seema R Lalani; Elsa Leitão; Anna Le Fevre; Richard J Leventer; Jan E Liebelt; Paul J Lockhart; Alan S Ma; Ellen F Macnamara; Taylor M Maurer; Hector R Mendez; Stephen B Montgomery; Marie-Cécile Nassogne; Serena Neumann; Melanie O'Leary; Elizabeth E Palmer; John Phillips; Georgia Pitsava; Ryan Pysar; Heidi L Rehm; Chloe M Reuter; Nicole Revencu; Angelika Riess; Rocio Rius; Lance Rodan; Tony Roscioli; Jill A Rosenfeld; Rani Sachdev; Cas Simons; Sanjay M Sisodiya; Penny Snell; Laura St Clair; Zornitza Stark; Tiong Yang Tan; Natalie B Tan; Suzanna El Temple; David R Thorburn; Cynthia J Tifft; Eloise Uebergang; Grace E VanNoy; Eric Vilain; David H Viskochil; Laura Wedd; Matthew T Wheeler; Susan M White; Monica Wojcik; Lynne A Wolfe; Zoe Wolfenson; Changrui Xiao; David Zocche; John L Rubenstein; Eirene Markenscoff-Papadimitriou; Sebastian M Fica; Diana Baralle; Christel Depienne; Daniel G MacArthur; Joanna Mm Howson; Stephan J Sanders; Anne O'Donnell-Luria; Nicola Whiffin

doi:10.1101/2024.04.07.24305438

De novo variants in the non-coding spliceosomal snRNA gene RNU4-2 are a frequent cause of syndromic neurodevelopmental disorders.

Yuyang Chen, Ruebena Dawes, Hyung Chul Kim, Sarah L Stenton, Susan Walker, Alicia Ljungdahl, Jenny Lord, Vijay S Ganesh, Jialan Ma, Alexandra C Martin-Geary, Gabrielle Lemire, Elston N D'Souza, Shan Dong, Jamie M Ellingford, David R Adams, Kirsten Allan, Madhura Bakshi, Erin E Baldwin, Seth I Berger, Jonathan A BernsteinNatasha J Brown, Lindsay C Burrage, Kimberly Chapman, Alison G Compton, Chloe A Cunningham, Precilla D'Souza, Emmanuèle C Délot, Kerith-Rae Dias, Ellen R Elias, Carey-Anne Evans, Lisa Ewans, Kimberly Ezell, Jamie L Fraser, Lyndon Gallacher, Casie A Genetti, Christina L Grant, Tobias Haack, Alma Kuechler, Seema R Lalani, Elsa Leitão, Anna Le Fevre, Richard J Leventer, Jan E Liebelt, Paul J Lockhart, Alan S Ma, Ellen F Macnamara, Taylor M Maurer, Hector R Mendez, Stephen B Montgomery, Marie-Cécile Nassogne, Serena Neumann, Melanie O'Leary, Elizabeth E Palmer, John Phillips, Georgia Pitsava, Ryan Pysar, Heidi L Rehm, Chloe M Reuter, Nicole Revencu, Angelika Riess, Rocio Rius, Lance Rodan, Tony Roscioli, Jill A Rosenfeld, Rani Sachdev, Cas Simons, Sanjay M Sisodiya, Penny Snell, Laura St Clair, Zornitza Stark, Tiong Yang Tan, Natalie B Tan, Suzanna El Temple, David R Thorburn, Cynthia J Tifft, Eloise Uebergang, Grace E VanNoy, Eric Vilain, David H Viskochil, Laura Wedd, Matthew T Wheeler, Susan M White, Monica Wojcik, Lynne A Wolfe, Zoe Wolfenson, Changrui Xiao, David Zocche, John L Rubenstein, Eirene Markenscoff-Papadimitriou, Sebastian M Fica, Diana Baralle, Christel Depienne, Daniel G MacArthur, Joanna Mm Howson, Stephan J Sanders, Anne O'Donnell-Luria, Nicola Whiffin

Research output: Contribution to journal › Article

Abstract

Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes 1 . Increasingly, 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 novel 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 spliceosome 2 . 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 119 individuals with NDD. The vast majority of individuals (77.3%) have the same highly recurrent single base-pair insertion (n.64_65insT). We estimate that variants in this region explain 0.41% of individuals with NDD. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to its contiguous counterpart RNU4-1 and other U4 homologs, supporting RNU4-2 's role as the primary U4 transcript in the brain. Overall, this work underscores the importance of non-coding genes in rare disorders. It will provide a diagnosis to thousands of individuals with NDD worldwide and pave the way for the development of effective treatments for these individuals.

Original language	English
Journal	medRxiv
DOIs	https://doi.org/10.1101/2024.04.07.24305438
Publication status	Published - 9 Apr 2024

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10.1101/2024.04.07.24305438

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Chen, Y., Dawes, R., Kim, H. C., Stenton, S. L., Walker, S., Ljungdahl, A., Lord, J., Ganesh, V. S., Ma, J., Martin-Geary, A. C., Lemire, G., D'Souza, E. N., Dong, S., Ellingford, J. M., Adams, D. R., Allan, K., Bakshi, M., Baldwin, E. E., Berger, S. I., ... Whiffin, N. (2024). De novo variants in the non-coding spliceosomal snRNA gene RNU4-2 are a frequent cause of syndromic neurodevelopmental disorders. medRxiv. https://doi.org/10.1101/2024.04.07.24305438

@article{de15a2999ec649e2b267d1a10786a149,

title = "De novo variants in the non-coding spliceosomal snRNA gene RNU4-2 are a frequent cause of syndromic neurodevelopmental disorders.",

abstract = "Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes 1 . Increasingly, 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 novel 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 spliceosome 2 . 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 119 individuals with NDD. The vast majority of individuals (77.3%) have the same highly recurrent single base-pair insertion (n.64_65insT). We estimate that variants in this region explain 0.41% of individuals with NDD. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to its contiguous counterpart RNU4-1 and other U4 homologs, supporting RNU4-2 's role as the primary U4 transcript in the brain. Overall, this work underscores the importance of non-coding genes in rare disorders. It will provide a diagnosis to thousands of individuals with NDD worldwide and pave the way for the development of effective treatments for these individuals. ",

author = "Yuyang Chen and Ruebena Dawes and Kim, {Hyung Chul} and Stenton, {Sarah L} and Susan Walker and Alicia Ljungdahl and Jenny Lord and Ganesh, {Vijay S} and Jialan Ma and Martin-Geary, {Alexandra C} and Gabrielle Lemire and D'Souza, {Elston N} and Shan Dong and Ellingford, {Jamie M} and Adams, {David R} and Kirsten Allan and Madhura Bakshi and Baldwin, {Erin E} and Berger, {Seth I} and Bernstein, {Jonathan A} and Brown, {Natasha J} and Burrage, {Lindsay C} and Kimberly Chapman and Compton, {Alison G} and Cunningham, {Chloe A} and Precilla D'Souza and D{\'e}lot, {Emmanu{\`e}le C} and Kerith-Rae Dias and Elias, {Ellen R} and Carey-Anne Evans and Lisa Ewans and Kimberly Ezell and Fraser, {Jamie L} and Lyndon Gallacher and Genetti, {Casie A} and Grant, {Christina L} and Tobias Haack and Alma Kuechler and Lalani, {Seema R} and Elsa Leit{\~a}o and Fevre, {Anna Le} and Leventer, {Richard J} and Liebelt, {Jan E} and Lockhart, {Paul J} and Ma, {Alan S} and Macnamara, {Ellen F} and Maurer, {Taylor M} and Mendez, {Hector R} and Montgomery, {Stephen B} and Marie-C{\'e}cile Nassogne and Serena Neumann and Melanie O'Leary and Palmer, {Elizabeth E} and John Phillips and Georgia Pitsava and Ryan Pysar and Rehm, {Heidi L} and Reuter, {Chloe M} and Nicole Revencu and Angelika Riess and Rocio Rius and Lance Rodan and Tony Roscioli and Rosenfeld, {Jill A} and Rani Sachdev and Cas Simons and Sisodiya, {Sanjay M} and Penny Snell and Clair, {Laura St} and Zornitza Stark and Tan, {Tiong Yang} and Tan, {Natalie B} and Temple, {Suzanna El} and Thorburn, {David R} and Tifft, {Cynthia J} and Eloise Uebergang and VanNoy, {Grace E} and Eric Vilain and Viskochil, {David H} and Laura Wedd and Wheeler, {Matthew T} and White, {Susan M} and Monica Wojcik and Wolfe, {Lynne A} and Zoe Wolfenson and Changrui Xiao and David Zocche and Rubenstein, {John L} and Eirene Markenscoff-Papadimitriou and Fica, {Sebastian M} and Diana Baralle and Christel Depienne and MacArthur, {Daniel G} and Howson, {Joanna Mm} and Sanders, {Stephan J} and Anne O'Donnell-Luria and Nicola Whiffin",

year = "2024",

month = apr,

day = "9",

doi = "10.1101/2024.04.07.24305438",

language = "English",

journal = "medRxiv",

publisher = "Cold Spring Harbor Laboratory Press",

}

Chen, Y, Dawes, R, Kim, HC, Stenton, SL, Walker, S, Ljungdahl, A, Lord, J, Ganesh, VS, Ma, J, Martin-Geary, AC, Lemire, G, D'Souza, EN, Dong, S, Ellingford, JM, Adams, DR, Allan, K, Bakshi, M, Baldwin, EE, Berger, SI, Bernstein, JA, Brown, NJ, Burrage, LC, Chapman, K, Compton, AG, Cunningham, CA, D'Souza, P, Délot, EC, Dias, K-R, Elias, ER, Evans, C-A, Ewans, L, Ezell, K, Fraser, JL, Gallacher, L, Genetti, CA, Grant, CL, Haack, T, Kuechler, A, Lalani, SR, Leitão, E, Fevre, AL, Leventer, RJ, Liebelt, JE, Lockhart, PJ, Ma, AS, Macnamara, EF, Maurer, TM, Mendez, HR, Montgomery, SB, Nassogne, M-C, Neumann, S, O'Leary, M, Palmer, EE, Phillips, J, Pitsava, G, Pysar, R, Rehm, HL, Reuter, CM, Revencu, N, Riess, A, Rius, R, Rodan, L, Roscioli, T, Rosenfeld, JA, Sachdev, R, Simons, C, Sisodiya, SM, Snell, P, Clair, LS, Stark, Z, Tan, TY, Tan, NB, Temple, SE, Thorburn, DR, Tifft, CJ, Uebergang, E, VanNoy, GE, Vilain, E, Viskochil, DH, Wedd, L, Wheeler, MT, White, SM, Wojcik, M, Wolfe, LA, Wolfenson, Z, Xiao, C, Zocche, D, Rubenstein, JL, Markenscoff-Papadimitriou, E, Fica, SM, Baralle, D, Depienne, C, MacArthur, DG, Howson, JM, Sanders, SJ, O'Donnell-Luria, A & Whiffin, N 2024, 'De novo variants in the non-coding spliceosomal snRNA gene RNU4-2 are a frequent cause of syndromic neurodevelopmental disorders.', medRxiv. https://doi.org/10.1101/2024.04.07.24305438

TY - JOUR

T1 - De novo variants in the non-coding spliceosomal snRNA gene RNU4-2 are a frequent cause of syndromic neurodevelopmental disorders.

AU - Chen, Yuyang

AU - Dawes, Ruebena

AU - Kim, Hyung Chul

AU - Stenton, Sarah L

AU - Walker, Susan

AU - Ljungdahl, Alicia

AU - Lord, Jenny

AU - Ganesh, Vijay S

AU - Ma, Jialan

AU - Martin-Geary, Alexandra C

AU - Lemire, Gabrielle

AU - D'Souza, Elston N

AU - Dong, Shan

AU - Ellingford, Jamie M

AU - Adams, David R

AU - Allan, Kirsten

AU - Bakshi, Madhura

AU - Baldwin, Erin E

AU - Berger, Seth I

AU - Bernstein, Jonathan A

AU - Brown, Natasha J

AU - Burrage, Lindsay C

AU - Chapman, Kimberly

AU - Compton, Alison G

AU - Cunningham, Chloe A

AU - D'Souza, Precilla

AU - Délot, Emmanuèle C

AU - Dias, Kerith-Rae

AU - Elias, Ellen R

AU - Evans, Carey-Anne

AU - Ewans, Lisa

AU - Ezell, Kimberly

AU - Fraser, Jamie L

AU - Gallacher, Lyndon

AU - Genetti, Casie A

AU - Grant, Christina L

AU - Haack, Tobias

AU - Kuechler, Alma

AU - Lalani, Seema R

AU - Leitão, Elsa

AU - Fevre, Anna Le

AU - Leventer, Richard J

AU - Liebelt, Jan E

AU - Lockhart, Paul J

AU - Ma, Alan S

AU - Macnamara, Ellen F

AU - Maurer, Taylor M

AU - Mendez, Hector R

AU - Montgomery, Stephen B

AU - Nassogne, Marie-Cécile

AU - Neumann, Serena

AU - O'Leary, Melanie

AU - Palmer, Elizabeth E

AU - Phillips, John

AU - Pitsava, Georgia

AU - Pysar, Ryan

AU - Rehm, Heidi L

AU - Reuter, Chloe M

AU - Revencu, Nicole

AU - Riess, Angelika

AU - Rius, Rocio

AU - Rodan, Lance

AU - Roscioli, Tony

AU - Rosenfeld, Jill A

AU - Sachdev, Rani

AU - Simons, Cas

AU - Sisodiya, Sanjay M

AU - Snell, Penny

AU - Clair, Laura St

AU - Stark, Zornitza

AU - Tan, Tiong Yang

AU - Tan, Natalie B

AU - Temple, Suzanna El

AU - Thorburn, David R

AU - Tifft, Cynthia J

AU - Uebergang, Eloise

AU - VanNoy, Grace E

AU - Vilain, Eric

AU - Viskochil, David H

AU - Wedd, Laura

AU - Wheeler, Matthew T

AU - White, Susan M

AU - Wojcik, Monica

AU - Wolfe, Lynne A

AU - Wolfenson, Zoe

AU - Xiao, Changrui

AU - Zocche, David

AU - Rubenstein, John L

AU - Markenscoff-Papadimitriou, Eirene

AU - Fica, Sebastian M

AU - Baralle, Diana

AU - Depienne, Christel

AU - MacArthur, Daniel G

AU - Howson, Joanna Mm

AU - Sanders, Stephan J

AU - O'Donnell-Luria, Anne

AU - Whiffin, Nicola

PY - 2024/4/9

Y1 - 2024/4/9

N2 - Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes 1 . Increasingly, 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 novel 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 spliceosome 2 . 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 119 individuals with NDD. The vast majority of individuals (77.3%) have the same highly recurrent single base-pair insertion (n.64_65insT). We estimate that variants in this region explain 0.41% of individuals with NDD. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to its contiguous counterpart RNU4-1 and other U4 homologs, supporting RNU4-2 's role as the primary U4 transcript in the brain. Overall, this work underscores the importance of non-coding genes in rare disorders. It will provide a diagnosis to thousands of individuals with NDD worldwide and pave the way for the development of effective treatments for these individuals.

AB - Around 60% of individuals with neurodevelopmental disorders (NDD) remain undiagnosed after comprehensive genetic testing, primarily of protein-coding genes 1 . Increasingly, 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 novel 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 spliceosome 2 . 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 119 individuals with NDD. The vast majority of individuals (77.3%) have the same highly recurrent single base-pair insertion (n.64_65insT). We estimate that variants in this region explain 0.41% of individuals with NDD. We demonstrate that RNU4-2 is highly expressed in the developing human brain, in contrast to its contiguous counterpart RNU4-1 and other U4 homologs, supporting RNU4-2 's role as the primary U4 transcript in the brain. Overall, this work underscores the importance of non-coding genes in rare disorders. It will provide a diagnosis to thousands of individuals with NDD worldwide and pave the way for the development of effective treatments for these individuals.

U2 - 10.1101/2024.04.07.24305438

DO - 10.1101/2024.04.07.24305438

M3 - Article

C2 - 38645094

JO - medRxiv

JF - medRxiv

ER -

De novo variants in the non-coding spliceosomal snRNA gene RNU4-2 are a frequent cause of syndromic neurodevelopmental disorders.

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