Systematic analysis of snRNA genes reveals frequent RNU2-2 variants in dominant and recessive developmental and epileptic encephalopathies
Leitão 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 J-M., 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., Bézieau S., Bhouri R., Biehler M., Hammer TB., Bogoin J., Bonanno E., Boussion S., Bris C., Brosseau-Beauvir A., Bruel A-L., 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 A-C., Dang LT., de Saint Martin A., de Vanssay de Blavous Legendre C., Demeer B., Denommé-Pichon A-S., 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., Géraud J., Gill D., Goldenberg A., Grabli D., Grisel C., Gueden S., Gueguen P., Guerrot A-M., Guichet A., Haack TB., Härting N., Häusler MG., Heide S., Herget T., Héron B., Héron D., Herwig J., Heulin M., Holling T., Houdayer C., Isidor B., Jacquette A., Januel L., Jean-Marçais N., Kaiser FJ., Kaya S., King C., Konyukh M., Kraft F., Krause J., Kirstetter R., Kuechler A., Kurth I., Kutsche K., Labalme A., Laloy J-S., Laugel V., Le Bricquir F., Lèbre A-S., Lebrun M., Leguern E., Levy J., Lieffering N., Lyonnet S., Lüthy 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., Õunap K., Pais LS., Panagiotakaki E., Patat O., Perrin-Sabourin L., Petit F., Philippe C., Piton A., Planes M., Poirsier C., Pouzet A., Prouteau C., Quéméner-Redon S., Renaud M., Richard A-C., 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.
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.