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Further characterization of the BRSK2-associated neurodevelopmental disorder.

European journal of human genetics : EJHG

Authors: Palak Singhal, Tzung-Chien Hsieh, Nadja Ehmke, Elena Bacchelli, Marta Viggiano, Elena Maestrini, Paola Visconti, Annio Posar, Maria Cristina Scaduto, Alessandro Vaisfeld, Carey Ronspies, Sarah Burke, Joana Rosmaninho Salgado, Joaquim Sá, Sara Ribeiro, Amelle Shillington, Anjali Aggarwal, Christina Dailey, Carol Saunders, Florencia Del Viso, Chaya N Murali, Melissa MacPherson, Oana Caluseriu, Alain Verloes, Jonathan Levy, Yline Capri, Hannah S Kemmer, Manuel Holtgrewe, Philip M Boone, Lance Rodan, Georgia Vasileiou, Melissa Pauly, André Reis, Isabella Herman, Ivy Johnson, Himanshu Goel, Ana Maria Rodriguez Barreto, Flavio Faletra, Catia Mio, Mona L Essawi, Heba A Hassan, Wessam E Sharaf-Eldin, Nirmeen Kishk, Giuseppe Donato Mangano, Renata Mangano, Andrea K Shields, Judith D Ranells, Trine Bjørg Hammer, Clara Velmans, Christian Netzer, Nora Winnerling, Konstantinos Kolokotronis, Benjamin Seidl, Anita Rauch, Alberto Fernandez-Jaen, Aboulfazl Rad, Gabriela Oprea, Paskal Cullufi, Sonila Tomori, Claire Beneteau, Marine Legendre, Caroline Rooryck, Hannah Klinkhammer, Tobias B Haack, Amjad Khan, Johanna Kick, Deborah Bartholdi, Dominique Braun, Erin E Baldwin, David H Viskochil, Lorenzo D Botto, Anna LaGroon, Emily Black, Kameryn M Butler, Emmanuelle Ranza, Manon Macherel, Vincent Desportes, Mathilde Pujalte, Louis Januel, Boris Keren, Cyril Mignot, Madeleine Harion, Maartje L E Voors, Charlotte W Ockeloen, Javier Porta-Pelayo, Bernt Popp, Peter Krawitz, Heinrich Sticht, Anne Gregor, Christiane Zweier

Variants in BRSK2, encoding brain specific kinase-2, have recently been associated with an autosomal dominant neurodevelopmental disorder (NDD). We have assembled 52 cases with heterozygous BRSK2 variants and variable neurodevelopmental phenotypes with frequent neuropsychiatric and behavioral symptoms. The variant spectrum included 15 different truncating variants, seven (potential) splice variants, three structural variants, and 12 different missense variants. Of the missense variants, seven were in the kinase domain, and the others in the UBA and the KA1 domain or outside domains. Variants occurred de novo in 19 cases and were inherited in 18. We utilized Drosophila melanogaster as a model and assessed viability and performed climbing and bang sensitivity assays upon knockdown of the fly orthologue sff or upon overexpression of wildtype or mutant human BRSK2. Pan-neuronal knockdown of sff resulted in impaired locomotor behavior and seizure susceptibility. Ubiquitous or pan-neuronal overexpression of human wildtype BRSK2 in Drosophila resulted in lethality or locomotor impairment, respectively, indicating toxicity. Overexpressing mutant BRSK2 did not or incompletely affect viability and locomotor behavior for six of seven tested kinase domain missense variants and one KA1 domain variant, indicating a (partial) loss-of-function effect. Interestingly, overexpressing BRSK2 with the remaining missense variant from the kinase domain and the two most C-terminal missense variants resulted in possible gain of function. Our findings further delineate the clinical and molecular spectrum of BRSK2-associated NDD and provide further insights into the role of BRSK2/sff in nervous system function and dysfunction.

© 2026. The Author(s).

PMID: 42509346

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