Monoallelic variants in BRSK1 are associated with a neurodevelopmental disorder with or without epilepsy

Brain-specific serine/threonine kinase (BRSK1; synapses of amphids defective [SAD]-B) encodes an AMP-activated protein kinase (AMPK)-related serine/threonine kinase required for neuronal polarization and synaptic function. An individual with a variant in BRSK1 was identified in the Texome Project, which provides genomic diagnosis to financially disadvantaged individuals in Texas, using AI-MARRVEL. We subsequently found nine individuals harboring rare heterozygous BRSK1 variants through GeneMatcher. Affected individuals present with developmental delay and variable phenotypes including anxiety, attention-deficit hyperactivity disorder (ADHD), autism, and seizures. All variants (missense and nonsense) are predicted to be deleterious by pathogenicity prediction tools. We utilized Drosophila to model three missense variants to assess the impact of the variants in vivo. We show that Drosophila sff (sugar-free frosting; ortholog of BRSK1) is expressed in neurons of the larval central nervous system (CNS) and adult brain. Loss of sff leads to viable flies with severe locomotor impairment, bang and heat sensitivity, and a short lifespan. In addition, the third-instar neuromuscular junctions (NMJs) in sff null mutants display a significant overgrowth, associated with elevated levels of Futsch (MAP1B), a microtubule-associated protein. Expression of the human reference BRSK1 cDNA in the sff null mutant rescues the behavioral, NMJ morphology, and Futsch phenotypes, showing that the human gene is functional in flies. In contrast, the three individual-derived alleles (BRSK1^p.Ile202Val, BRSK1^p.Arg237Cys, and BRSK1^p.Thr406Ile) provide only a partial rescue and fail to normalize NMJ morphology and Futsch levels, suggesting that they are partial loss-of-function alleles. In summary, our data support a model that heterozygous loss of BRSK1 leads to a neurodevelopmental syndrome with variable phenotypes.