Further characterization of the BRSK2-associated neurodevelopmental disorder

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.

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Journal
European Journal of Human Genetics
Published
2026-07-27
DOI
https://doi.org/10.1038/s41431-026-02195-7
Primary Topic
Genomics and Rare Diseases
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article
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article

Further characterization of the BRSK2-associated neurodevelopmental disorder

Alain Verloès, Oana Caluseriu, M. Pauly, Elena Bacchelli et al.
European Journal of Human Genetics
Genomics and Rare Diseases
article

Further characterization of the BRSK2-associated neurodevelopmental disorder

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

Abstract

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.

European Journal of Human Genetics
Université Claude Bernard Lyon 1 (FR), Broad Institute (US), University of Bern (CH), Alberta Health Services (CA), Cincinnati Children's Hospital Medical Center (US), Boston Children's Hospital (US), University of Udine (IT), University of Minnesota (US), Bern University of Applied Sciences (CH), Nebraska Medical Center (US), Children's Mercy Hospital (US), University of Bonn (DE), Harvard University (US), Cairo University (EG), Radboud University Nijmegen (NL), University of Alberta (CA), Zimmer Biomet (Netherlands) (NL), Friedrich-Alexander-Universität Erlangen-Nürnberg (DE), Baylor College of Medicine (US), University of Zurich (CH), Université Paris Cité (FR), University of Utah (US), Università degli Studi di Enna Kore (IT), University of South Florida (US), Mother Teresa Hospital (AL), University Hospital of Bern (CH), Hospitais da Universidade de Coimbra (PT), Copenhagen University Hospital (DK), Radboud University Medical Center (NL), Government of Khyber Pakhtunkhwa (PK), Centre Hospitalier Universitaire de Bordeaux (FR), ETH Zurich (CH), Humboldt-Universität zu Berlin (DE), Sorbonne Université (FR), Hôpital Armand-Trousseau (FR), Massachusetts General Hospital (US), Universitätsklinikum Erlangen (DE), Assistance Publique – Hôpitaux de Paris (FR), Hunter Genetics (AU), Hospices Civils de Lyon (FR), Boys Town National Research Hospital (US), Hospital Universitario Quirónsalud Madrid (ES), Azienda USL di Bologna (IT), Istituto delle Scienze Neurologiche di Bologna (IT), Ospedale Santa Maria della Misericordia di Udine (IT), Hôpital Robert-Debré (FR), University Centre of Legal Medicine (CH), National Research Centre (EG), Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE), Miami Children's Hospital (US), Greenwood Genetic Center (US), Istituti di Ricovero e Cura a Carattere Scientifico (IT), University Hospital Cologne (DE), University of Nebraska Medical Center (US), University of Missouri–Kansas City (US), Freie Universität Berlin (DE), Charité - Universitätsmedizin Berlin (DE), University of Tübingen (DE), Universidad de Málaga (ES), University of Palermo (IT), Universidad Europea de Madrid (ES), Leipzig University (DE), University of Bologna (IT), HCL Technologies (India) (IN)
Foundation for the National Institutes of Health, European Commission, Deutsche Forschungsgemeinschaft, Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung, National Institute of Neurological Disorders and Stroke
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Genomics and Rare Diseases
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