PURPOSE: Biallelic variants in the minor spliceosomal gene RNU4ATAC were successively identified in Taybi-Linder/Microcephalic osteodysplastic primordial dwarfism type I, Roifman, and Lowry-Wood syndromes, which are 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 or atypical presentations, novel rare symptoms, and, unexpectedly, a broad spectrum of autoimmune or 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 that is distinct among some sub-syndromes.
CONCLUSION
We present a large cohort of individuals with RNU4ATAC-opathies and expand the phenotypic spectrum to paucisymptomatic forms, indicating that these diseases are likely to remain underdiagnosed.
Для цитирования: Cuinat Silvestre, Cormier-Daire Valérie, Rosain Jeremie, Huber Céline, Ferriere Elsa, Fournier Benjamin, Cheminant Morgane, Castelle Martin, Bastard Paul, Noel Nicolas, Bourdic Katia, Picard Capucine, Moshous Despina, Courteille Virginie, Mahlaoui Nizar, Bustamante Jacinta, Collobert Gislène, Mignot Cyril, Keren Boris, Drunat Séverine, Rondeau Sophie, Rabec Alexia, Besson Alicia, Chatron Nicolas, Lesca Gaetan, Laurent Audrey, Mortreux Jérémie, Dancer Marine Serveaux, Dejeans Gabriel, Poggi Claire, Stoeva Radka, Lecordier Alissandre, Poirsier Céline, Dieux Anne, Sarrot-Reynauld Francoise, Laudier Béatrice, Le Besnerais Maelle, Guerrot Anne-Marie, Nizon Mathilde, Cogne Benjamin, Isidor Bertrand, Julia Sophie, Bouri Sarra, Fusaro Mathieu, Willems Marjolaine, Elenga Narcisse, Remadji Dobian Succès, Diop Mody, Pacaud Salomé, Dichamp Claire, Sarrazin Elisabeth, Lasa-Aranzasti Amaia, Tizzano Eduardo Fidel, Cuscó Martí Ivon, Martín-Nalda Andrea, Felipe-Rucián Ana, Gómez-Andres David, Codina-Solà Marta, Fernandez Paula, Riviere Jacques Gabriel, Soler-Palacín Pere, Fernández-Jaén Alberto, Carrión-Mera Teresa, Borgmann Insa, Johnsen Christin, Schlotawa Lars, Kettwig Matthias, Hoffmann Jessica, Lex Christiane, Speckmann Carsten, von Hardenberg Sandra, Wetzke Martin, Paul Victoria G, Vockel Matthias, Horvath Judit, Busche Andreas, Hirschberger Niklas, Shoukier Moneef, Filges Isabel, De Geyter Julie, Barakat Tahsin Stefan, Borg Isabella, Kłosowska Anna, Głuszkiewicz Lena, Allen Stephanie, Cilliers Deirdre, Foley Patricia Ann, Lynch Sally Ann, McDonnell Ciara, Sansović Ivona, Odak Ljubica, Vulin Katarina, Jensen Janni Majgaard, Pedersen Inge Søkilde, Ernst Anja, Taşdelen Elifcan, Kılıç Mustafa, Kılıç Esra, Altunoğlu Umut, Tatlı Burak, Akman Burcu, Yıldırım Ravza Nur, Gürsoy Semra, Giray Bozkaya Özlem, Niceta Marcello, Mancini Cecilia, Ciolfi Andrea, Severi Giulia, Capelli Marilù, Melis Daniela, Onesimo Roberta, Leoni Chiara, Carli Diana, Mussa Alessandro, Zampino Giuseppe, Citterio Andrea, Graziano Claudio, Donati Ilaria, Accadia Maria, Bisceglia Luigi, Bruselles Alessandro, Tartaglia Marco, Barragán-Arévalo Tania, Boone Philip M, Nelson Ryan W, Cabet Sara, Arlt Annabelle, Hustinx Alexander, Klinkhammer Hannah, Krawitz Peter, Amiel Jeanne, AURAGEN consortium, Valenzuela Palafoll Irene, Suarez Felipe, Delous Marion, Mazoyer Sylvie, Edery Patrick, Putoux Audrey. Expanding the clinical spectrum of RNU4ATAC-opathies: More frequent and diverse than assumed.. Genetics in medicine : official journal of the American College of Medical Genetics. 2026. DOI: 10.1016/j.gim.2026.102632.
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