Systematic analysis of snRNA genes reveals frequent RNU2-2 variants in dominant and recessive developmental and epileptic encephalopathies

Leitao, E; Santini, A; Cogne, B; Essid, M; Athanasiadou, M; LaFlamme, CW; Marijon, P; Bernard, V; Jousselin, K; Chatron, N; Barcia, G; Keren, B; Mignot, C; Charles, P; Besnard, T; Paluch, R; de Sainte Agathe, JM; Almanza Fuerte, EP; Sengupta, S; Milh, M; Ramond, F; Allan, T; An, I; Araujo, C; Arpin, S; Austin-Tse, C; Auvin, S; Baer, S; Bahi-Buisson, N; Bak, M; Barth, M; Baulac, S; Bednarek-Weirauch, N; Begemann, M; Bennett, MF; Bensabath, U; Bezieau, S; Bhouri, R; Biehler, M; Hammer, TB; Bogoin, J; Bonanno, E; Boussion, S; Bris, C; Brosseau-Beauvir, A; Bruel, AL; Briand-Suleau, A; Buratti, J; Celse, T; CHAMBON, P; Chemaly, N; Chesneau, B; Colin, E; Colmard, M; Colson, C; Conrad, S; Courtin, T; Creveaux, I; Cullier, AC; Dang, LT; de Saint Martin, A; de Vanssay de Blavous Legendre, C; Demeer, B; Denomme-Pichon, AS; Diekhoff, P; DiTroia, S; Doco-Fenzy, M; Dubourg, C; Dubucs, C; Ducreux, S; Dufour, L; Duquet, R; Durand, B; El Chehadeh, S; Elbracht, M; Faivre, L; Faoucher, M; Faudet, A; Forlani, S; Fradin, M; Gaignard, P; Ganne, B; Garde, A; Geraud, J; Gill, D; Goldenberg, A; Grabli, D; Grisel, C; Gueden, S; Gueguen, P; Guerrot, AM; Guichet, A; Haack, TB; Harting, N; Hausler, MG; Heide, S; Herget, T; Heron, B; Heron, D; Herwig, J; Heulin, M; Holling, T; Houdayer, C; Isidor, B; Jacquette, A; Januel, L; Jean-Marcais, N; Kaiser, FJ; Kaya, S; King, C; Konyukh, M; Kraft, F; Krause, J; Kirstetter, R; Kuechler, A; Kurth, I; Kutsche, K; Labalme, A; Laloy, JS; Laugel, V; Le Bricquir, F; Lebre, AS; Lebrun, M; LeGuern, E; Levy, J; Lieffering, N; Lyonnet, S; Luthy, K; Macdonald, SMW; Mansour-Hendili, L; Maraval, J; Marquardt, I; Mattausch, C; Mercier, S; Messaoud, O; Morel, G; Mortreux, J; Munnich, A; Nabbout, R; Nambot, S; Navarro, V; Neale, A; Nguyen, L; Nizon, M; Nowak, F; O&#39;Leary, MC; Odent, S; Ojeda, NM; Olin, V; Olivieri, S; Ounap, K; Pais, LS; Panagiotakaki, E; Patat, O; Perrin-Sabourin, L; Petit, F; Philippe, C; Piton, A; Planes, M; Poirsier, C; Pouzet, A; Prouteau, C; Quemener-Redon, S; Renaud, M; Richard, AC; Rio, M; Rivier, C; Robin-Renaldo, F; Rollier, P; Rossi, M; Roubertie, A; Ruault, V; Rupin-Mas, M; Saugier-Veber, P; Saunier, A; Saneto, R; Sarrazin, E; Sarret, C; Schaefer, E; Schluth-Bolard, C; Schneider, A; Schumann, I; Seplyarskiy, VB; Spranger, S; Smol, T; Sturm, M; Sunyaev, SR; Sperelakis-Beedham, B; Stenton, SL; Stock, F; Tharreau, M; Torun, D; Toulouse, J; Thiyagarajah, H; Valence, S; Valleix, S; Van-Gils, J; Villard, L; Ville, D; Villeneuve, N; Vitobello, A; Waernessyckle, A; Wagner, J; Weber, Y; Wieczorek, D; Witkowski, T; Yadavilli, M; Yammine, T; Zaafrane-Khachnaoui, K; Zaki, MS; Ziegler, A; Bramswig, NC; Lermine, A; Nicolas, G; Gleeson, JG; Sadleir, LG; Hildebrand, MS; Scheffer, IE; Whiffin, N; O&#39;Donnell-Luria, A; Mefford, HC; Blanc, P; Thevenon, J; Charbonnier, C; Charenton, C; Depienne, C; Lesca, G; Nava, C

Author(s): Leitao, E; Santini, A; Cogne, B; Essid, M; Athanasiadou, M; LaFlamme, CW; Marijon, P; Bernard, V; Jousselin, K; Chatron, N; Barcia, G; Keren, B; Mignot, C; Charles, P; Besnard, T; Paluch, R; de Sainte Agathe, JM; Almanza Fuerte, EP; Sengupta, S; Milh, M; Ramond, F; Allan, T; An, I; Araujo, C; Arpin, S; Austin-Tse, C; Auvin, S; Baer, S; Bahi-Buisson, N; Bak, M; Barth, M; Baulac, S; Bednarek-Weirauch, N; Begemann, M; Bennett, MF; Bensabath, U; Bezieau, S; Bhouri, R; Biehler, M; Hammer, TB; Bogoin, J; Bonanno, E; Boussion, S; Bris, C; Brosseau-Beauvir, A; Bruel, AL; Briand-Suleau, A; Buratti, J; Celse, T; CHAMBON, P; Chemaly, N; Chesneau, B; Colin, E; Colmard, M; Colson, C; Conrad, S; Courtin, T; Creveaux, I; Cullier, AC; Dang, LT; de Saint Martin, A; de Vanssay de Blavous Legendre, C; Demeer, B; Denomme-Pichon, AS; Diekhoff, P; DiTroia, S; Doco-Fenzy, M; Dubourg, C; Dubucs, C; Ducreux, S; Dufour, L; Duquet, R; Durand, B; El Chehadeh, S; Elbracht, M; Faivre, L; Faoucher, M; Faudet, A; Forlani, S; Fradin, M; Gaignard, P; Ganne, B; Garde, A; Geraud, J; Gill, D; Goldenberg, A; Grabli, D; Grisel, C; Gueden, S; Gueguen, P; Guerrot, AM; Guichet, A; Haack, TB; Harting, N; Hausler, MG; Heide, S; Herget, T; Heron, B; Heron, D; Herwig, J; Heulin, M; Holling, T; Houdayer, C; Isidor, B; Jacquette, A; Januel, L; Jean-Marcais, N; Kaiser, FJ; Kaya, S; King, C; Konyukh, M; Kraft, F; Krause, J; Kirstetter, R; Kuechler, A; Kurth, I; Kutsche, K; Labalme, A; Laloy, JS; Laugel, V; Le Bricquir, F; Lebre, AS; Lebrun, M; LeGuern, E; Levy, J; Lieffering, N; Lyonnet, S; Luthy, K; Macdonald, SMW; Mansour-Hendili, L; Maraval, J; Marquardt, I; Mattausch, C; Mercier, S; Messaoud, O; Morel, G; Mortreux, J; Munnich, A; Nabbout, R; Nambot, S; Navarro, V; Neale, A; Nguyen, L; Nizon, M; Nowak, F; O'Leary, MC; Odent, S; Ojeda, NM; Olin, V; Olivieri, S; Ounap, K; Pais, LS; Panagiotakaki, E; Patat, O; Perrin-Sabourin, L; Petit, F; Philippe, C; Piton, A; Planes, M; Poirsier, C; Pouzet, A; Prouteau, C; Quemener-Redon, S; Renaud, M; Richard, AC; Rio, M; Rivier, C; Robin-Renaldo, F; Rollier, P; Rossi, M; Roubertie, A; Ruault, V; Rupin-Mas, M; Saugier-Veber, P; Saunier, A; Saneto, R; Sarrazin, E; Sarret, C; Schaefer, E; Schluth-Bolard, C; Schneider, A; Schumann, I; Seplyarskiy, VB; Spranger, S; Smol, T; Sturm, M; Sunyaev, SR; Sperelakis-Beedham, B; Stenton, SL; Stock, F; Tharreau, M; Torun, D; Toulouse, J; Thiyagarajah, H; Valence, S; Valleix, S; Van-Gils, J; Villard, L; Ville, D; Villeneuve, N; Vitobello, A; Waernessyckle, A; Wagner, J; Weber, Y; Wieczorek, D; Witkowski, T; Yadavilli, M; Yammine, T; Zaafrane-Khachnaoui, K; Zaki, MS; Ziegler, A; Bramswig, NC; Lermine, A; Nicolas, G; Gleeson, JG; Sadleir, LG; Hildebrand, MS; Scheffer, IE; Whiffin, N; O'Donnell-Luria, A; Mefford, HC; Blanc, P; Thevenon, J; Charbonnier, C; Charenton, C; Depienne, C; Lesca, G; Nava, C;
Details: Publication Year 2026-04,Volume 58,Issue #4,Page 782-797
Journal Title: Nature Genetics
Publication Type: Mar 30
Abstract: Small nuclear RNAs (snRNAs) are essential components of the spliceosome. De novo variants in snRNA genes RNU4-2 (ReNU syndrome), RNU5B-1 and RNU2-2 have been linked to dominant neurodevelopmental disorders (NDDs), revealing a large unexpected contribution of noncoding RNA genes to genetic diseases. Here, through international collaborations, we analyze systematically 200 potentially functional snRNA genes in a French cohort of 34,329 people with rare disorders. We report RNU2-2 variants in 141 individuals, including 35 with recurrent dominant pathogenic variants and 91 affected members from 73 families with biallelic variants. Recessive RNU2-2 NDD is at least twice as frequent as the dominant form and often involves a de novo variant in trans with an inherited allele, consistent with the high mutability of snRNA genes. Dominant and recessive RNU2-2 NDDs share overlapping clinical features, with frequent epilepsy. Blood transcriptomics and DNA methylation analyses revealed subtle, variant-specific effects on splicing and episignatures. Our results support a gradient-of-impact model bridging dominant and recessive inheritance, and establish RNU2-2 variants as a principal contributor to NDDs, nearly as prevalent as ReNU syndrome.
Publisher: Springer Nature
Keywords: Humans; *RNA, Small Nuclear/genetics; Genes, Recessive; Male; Female; *Epilepsy/genetics; Genes, Dominant; RNA Splicing; DNA Methylation/genetics; *Neurodevelopmental Disorders/genetics; Cohort Studies; Mutation; *Osteochondrodysplasias/genetics; Child; Pedigree; *Fetal Growth Retardation/genetics; Dwarfism; Microcephaly
Research Division(s): Genetics and Gene Regulation
PubMed ID: 41912934
Publisher's Version: https://doi.org/10.1038/s41588-026-02547-5
Open Access at Publisher's Site: https://doi.org/10.1038/s41588-026-02547-5
Terms of Use/Rights Notice: Refer to copyright notice on published article.

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