BRSK2 – Neurodevelopmental Disorder

BRSK2 (Gene Symbol) encodes a brain-specific serine/threonine kinase critical for neuronal polarization and axon formation. Heterozygous variants in BRSK2 have been implicated in a spectrum of neurodevelopmental phenotypes, including intellectual disability, developmental delay, and autism, under an autosomal dominant model. This summary focuses on the association between BRSK2 and neurodevelopmental disorder (Disease Name).

In a cohort spanning 3,429 probands, nine individuals with developmental delay and intellectual disability harbored heterozygous BRSK2 variants, all shown to arise de novo in six available parent–offspring trios ([PMID:30879638]). Six of these variants are predicted to result in loss of function, and three are missense changes with strong computational evidence for structural disruption ([PMID:30879638]). The observed rate of de novo variation in BRSK2 significantly exceeds the background mutation rate.

Further evidence arises from autism spectrum disorder cohorts, where 19 unrelated ASD patients carrying heterozygous BRSK2 variants have been reported, including a recurrent nonsense variant c.664C>T (p.Arg222Ter) studied in a zebrafish model ([PMID:37671287]; [PMID:35754711]). A novel de novo frameshift variant c.442del (p.Leu148CfsTer39) expanded the phenotype to include auditory hallucinations and limb tremor in a 16-year-old boy ([PMID:37671287]).

The variant spectrum comprises protein-truncating alleles (nonsense, frameshift, and splice-site) and rare missense substitutions. A representative missense example is c.194G>A (p.Arg65Gln), absent from population databases and predicted damaging by multiple algorithms. These variants cluster throughout the kinase domain, supporting a haploinsufficiency mechanism.

Functional studies in a brsk2b-deficient zebrafish line demonstrate embryonic lethality, developmental delay, pericardial edema, and ASD-like behaviors, including reduced social interaction and enhanced anxiety, accompanied by dysregulated expression of neurogenesis and myelination markers ([PMID:35754711]). These findings concord with the human phenotype and support a loss-of-function pathogenic mechanism.

Collectively, the genetic and experimental data provide strong evidence for BRSK2 haploinsufficiency as a cause of autosomal dominant neurodevelopmental disorder. BRSK2 should be included in diagnostic gene panels for NDD to facilitate early detection and intervention.

References

• American Journal of Human Genetics • 2019 • Deleterious Variation in BRSK2 Associates with a Neurodevelopmental Disorder. PMID:30879638
• Frontiers in molecular neuroscience • 2022 • Deleterious Variation in BR Serine/Threonine Kinase 2 Classified a Subtype of Autism. PMID:35754711
• Frontiers in psychiatry • 2023 • Case report: A novel frameshift mutation in BRSK2 causes autism in a 16-year old Chinese boy. PMID:37671287

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