Catatonia and regression in an autism spectrum disorder patient harbouring a <i>BRSK2</i> frameshift mutation.

Abstract

Deleterious variants in the <i>BRSK2</i> gene, which encodes a serine/threonine kinase crucial for neuronal polarisation and brain development, have recently been linked to the pathogenesis of autism spectrum disorder (ASD). However, comprehensive clinical descriptions of individuals with pathogenic <i>BRSK2</i> variants remain limited, and the molecular and cellular consequences of these mutations are poorly understood. This case report provides a detailed clinical, cognitive and molecular characterisation of a male patient with ASD harbouring a de novo <i>BRSK2</i> frameshift variant, who developed catatonia, developmental regression and cognitive decline during early adolescence. To assess the functional impact of the variant, induced pluripotent stem cells (iPSCs) and iPSC-derived neural organoids were generated from the patient. Molecular analyses revealed a significant reduction in <i>BRSK2</i> transcript and protein levels. Sequencing of <i>BRSK2</i> mRNA showed exclusive expression from the wild-type allele, consistent with degradation of the mutant transcript via nonsense-mediated decay. These findings broaden the mutational and phenotypic spectrum associated with <i>BRSK2</i>-related neurodevelopmental disorders and provide functional evidence supporting the pathogenicity of the identified variant. Furthermore, this report demonstrates the role of <i>BRSK2</i> in complex neuropsychiatric features-such as catatonia and cognitive deterioration, which remain underreported in the existing literature-and emphasises the importance of longitudinal cognitive and behavioural monitoring in individuals with <i>BRSK2</i> mutations.