Further characterization of the BRSK2-associated neurodevelopmental disorder

Singhal P, Hsieh TC, Ehmke N, Bacchelli E, Viggiano M, Maestrini E, Visconti P, Posar A, Scaduto MC, Vaisfeld A, Ronspies C, Burke S, Salgado JR, Sá J, Ribeiro S, Shillington A, Aggarwal A, Dailey C, Saunders C, Del Viso F, Murali CN, MacPherson M, Caluseriu O, Verloes A, Levy J, Capri Y, Kemmer HS, Holtgrewe M, Boone PM, Rodan L, Vasileiou G, Pauly M, Reis A, Herman I, Johnson I, Goel H, Rodriguez Barreto AM, Faletra F, Mio C, Essawi ML, Hassan HA, Sharaf-Eldin WE, Kishk N, Mangano GD, Mangano R, Shields AK, Ranells JD, Hammer TB, Velmans C, Netzer C, Winnerling N, Kolokotronis K, Seidl B, Rauch A, Fernandez-Jaen A, Rad A, Oprea G, Cullufi P, Tomori S, Beneteau C, Legendre M, Rooryck C, Klinkhammer H, Haack TB, Khan A, Kick J, Bartholdi D, Braun D, Baldwin EE, Viskochil DH, Botto LD, LaGroon A, Black E, Butler KM, Ranza E, Macherel M, Desportes V, Pujalte M, Januel L, Keren B, Mignot C, Harion M, Voors ML, Ockeloen CW, Porta-Pelayo J, Popp B, Krawitz P, Sticht H, Gregor A, Zweier C (2026)

Publication Type: Journal article

Publication year: 2026

Journal

DOI: 10.1038/s41431-026-02195-7

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.

Authors with CRIS profile

Involved external institutions

Boys Town National Research Hospital (BTNRH) United States (USA) (US) Baylor College of Medicine United States (USA) (US) University of Alberta Canada (CA) Université Sorbonne Paris Cité France (FR) Hunter Genetics Australia (AU) Nicklaus Children's Hospital United States (USA) (US) Ospedale Santa Maria della Misericordia di Udine Italy (IT) Charité - Universitätsmedizin Berlin Germany (DE) University of Udine / Università degli Studi di Udine Italy (IT) Berliner Institut für Gesundheitsforschung in der Charité / Berlin Institute of Health at Charité (BIH) Germany (DE) Harvard University United States (USA) (US) National Research Centre (NRC) / المركز القومي للبحوث Egypt (EG) Kore University of Enna / Università degli Studi di Enna Kore Italy (IT) Università degli Studi di Palermo Italy (IT) Morsani College of Medicine United States (USA) (US) Copenhagen University Hospital Denmark (DK) Universitätsklinikum Köln Germany (DE) University of Zurich / Universität Zürich (UZH) Switzerland (CH) Inselspital, Universitätsspital Bern Switzerland (CH) Rheinische Friedrich-Wilhelms-Universität Bonn Germany (DE) Hospital Universitario Quirónsalud Madrid Spain (ES) University of Bologna / Università di Bologna Italy (IT) Arcensus GmbH Germany (DE) IRCCS Istituto delle Scienze Neurologiche di Bologna (ISNB) Italy (IT) Mother Theresa University Hospital Center Albania (AL) Centre Hospitalier Universitaire de Bordeaux / CHU Bordeaux France (FR) University of Nebraska Medical Center (UNMC) United States (USA) (US) Eberhard Karls Universität Tübingen Germany (DE) Centro Hospitalar e Universitário de Coimbra (CHUC) Portugal (PT) Cincinnati Children's Hospital Medical Center United States (USA) (US) University of Minnesota (UMN) United States (USA) (US) Children's Mercy Hospital United States (USA) (US) University of Utah United States (USA) (US) Greenwood Genetic Center United States (USA) (US) Swiss Institute Of Genomic Medicine (medigenome) Switzerland (CH) Université de Lyon (UDL) France (FR) Hospices Civils de Lyon (CHU) France (FR) Pitié-Salpêtrière University Hospital / Hôpital universitaire Pitié-Salpêtrière France (FR) Hôpital Armand-Trousseau (AP-HP) France (FR) Radboud University Nijmegen Medical Centre / Radboudumc of voluit Radboud Universitair Medisch Centrum (UMC) Netherlands (NL) Genologica Médica Spain (ES)

How to cite

APA:

Singhal, P., Hsieh, T.C., Ehmke, N., Bacchelli, E., Viggiano, M., Maestrini, E.,... Zweier, C. (2026). Further characterization of the BRSK2-associated neurodevelopmental disorder. European Journal of Human Genetics. https://doi.org/10.1038/s41431-026-02195-7

MLA:

Singhal, Palak, et al. "Further characterization of the BRSK2-associated neurodevelopmental disorder." European Journal of Human Genetics (2026).

BibTeX: Download