Silvestre Cuinat, V. Cormier-Daire, J. Rosain, C. Huber, Elsa Ferrière, B. Fournier, M. Cheminant, M. Castelle, Paul Bastard, Nicolas Noel, K. Bourdic, C. Picard, D. Moshous, Virginie Courteille, N. Mahlaoui, J. Bustamante, G. Collobert, C. Mignot, B. Keren, S. Drunat, S. Rondeau, A. Rabec, A. Besson, N. Chatron, G. Lesca, A. Laurent, J. Mortreux, M. Dancer, Gabriel Dejeans, Claire Poggi, R. Stoeva, Alissandre Lecordier, C. Poirsier, A. Dieux, Françoise Sarrot-Reynauld, B. Laudier, M. Le Besnerais, A. Guerrot, M. Nizon, B. Cogné, Bertrand Isidor, S. Julia, Sarra Bouri, Mathieu Fusaro, Marjolaine Willems, N. Elenga, Succes Dobian, M. Diop, Salomé Pacaud, Claire Dichamp, Elisabeth Sarrazin, Amaia Lasa-Aranzasti, E. Tizzano, Ivon Cuscó Martí, A. M. Nalda, A. Felipe-Rucián, D. Gómez-Andrés, M. Codina-Solà, P. Fernández, J. G. Rivière, Pere Soler-Palacin, Alberto Fernández-Jaén, Teresa Carrión-Mera, I. Borgmann, Christin Johnsen, Lars Schlotawa, Matthias Kettwig, J. Hoffmann, C. Lex, C. Speckmann, Sandra von Hardenberg, M. Wetzke, Victoria G Paul, M. Vockel, Judit Horvath, Andreas Busche, N. Hirschberger, M. Shoukier, I. Filges, Julie De Geyter, T. S. Barakat, I. Borg, A. Kłosowska, L. Głuszkiewicz, S. Allen, De B. Cilliers, Patricia Foley, S. Lynch, Ciara M. McDonnell, I. Sansović, Ljubica Odak, Katarina Vulin, J. M. Jensen, I. S. Pedersen, Anja Ernst, Elifcan Taşdelen, Mustafa Kılıç, Esra Kılıç, U. Altunoğlu, B. Tatlı, Burcu Akman, Ravza Nur Yıldırım, S. Gürsoy, Ö. Bozkaya, M. Niceta, Cecilia Mancini, A. Ciolfi, Giulia Severi, M. Capelli, Daniela Melis, R. Onesimo, C. Leoni, Diana Carli, A. Mussa, G. Zampino, A. Citterio, C. Graziano, Ilaria Donati, Maria Accadia, L. Bisceglia, A. Bruselles, M. Tartaglia, Tania Barragán-Arévalo, Philip M. Boone, Ryan W. Nelson, S. Cabet, Annabelle Arlt, Alexander Hustinx, H. Klinkhammer, P. Krawitz, J. Amiel, Auragen Consortium, I. V. Palafoll, F. Suarez, M. Delous, Sylvie Mazoyer, P. Edery, A. Putoux
2026.6.19GENETICS IN MEDICINE
Abstract
PURPOSE: Biallelic variants in the minor spliceosomal gene RNU4ATAC were successively identified in Taybi-Linder/MOPD1 (Microcephalic osteodysplastic primordial dwarfism type I), Roifman, and Lowry-Wood syndromes, characterized by variable microcephaly, short stature, neurodevelopmental impairment, skeletal dysplasia, and immunodeficiency. Two-thirds of the reported individuals present with Taybi-Linder syndrome, the first described and most severe form. METHODS: We collected clinical and molecular data from individuals with biallelic RNU4ATAC variants through various French and European networks and clinics, to refine the phenotypic spectrum of RNU4ATAC-opathies. RESULTS: We enrolled 69 participants and identified 18 new pathogenic variants. We report a significant proportion of attenuated/atypical presentations, novel rare symptoms, and, unexpectedly, a broad spectrum of autoimmune/inflammatory manifestations, affecting nearly half of the participants. Integrating our data with the 109 published cases, we propose a novel classification based on the main manifestations, immunodeficiency and microcephalic primordial dwarfism. Using computer-assisted facial analysis, we also demonstrated the existence of a specific dysmorphic pattern in RNU4ATAC-opathies, distinct between some sub-syndromes. CONCLUSION: We present a large cohort of individuals with RNU4ATAC-opathies and expand the phenotypic spectrum to pauci-symptomatic forms, indicating that these diseases are likely to remain underdiagnosed.
Citation format
CUINAT, Silvestre, et al. Expanding the clinical spectrum of rnu4atac-opathies: More frequent and diverse than assumed. GENETICS IN MEDICINE, 2026: 102632.