GSK3B – Neurodevelopmental Disorder

Glycogen synthase kinase-3β (GSK3B) is a ubiquitously expressed serine/threonine kinase with critical roles in neuronal proliferation, differentiation, and synaptic formation. An integrative analysis of de novo single-nucleotide and copy-number variants in 41 165 individuals with neurodevelopmental disorders highlighted a significant enrichment of deleterious GSK3B variants, ranking it among 34 novel candidate genes (PMID:35468861). Subsequent multicenter sequencing in autism spectrum disorder (ASD) cohorts identified 15 unrelated probands with de novo potential splicing-disrupting variants in GSK3B, all presenting with global developmental delay, ASD, sleep disturbance, and aggressive behavior (PMID:39472663).

Inheritance is autosomal dominant with heterozygous loss-of-function (LoF) as the likely mechanism. All reported variants were de novo, and no extended familial segregation has been described. The cohort comprised exclusively simplex cases, aligning with a de novo mutational model and absence of additional affected relatives.

Genetic evidence includes 15 probands with splicing-disrupting GSK3B variants demonstrating a significant case burden versus unaffected siblings. Variant classes are predominantly intronic PSDVs predicted to abrogate canonical splicing, consistent with a LoF spectrum. No recurrent or founder alleles have yet been reported.

Functional studies support a haploinsufficiency mechanism. GSK3B expression is enriched in dorsal progenitors and intermediate excitatory neurons in the developing human cortex. In vivo Gsk3b knockdown in mouse excitatory neurons impairs dendritic arborization and spine maturation, phenocopying aspects of the human neurodevelopmental phenotype (PMID:39472663).

Collectively, de novo LoF variants in GSK3B compromise neuronal structure and function through reduced kinase activity and downstream signaling perturbation. The integration of large-scale human genetics and concordant mouse models provides strong clinical validity for GSK3B in autosomal dominant neurodevelopmental disorder.

Key Take-home: Heterozygous loss-of-function variants in GSK3B cause a definable neurodevelopmental syndrome with developmental delay and ASD, warranting inclusion in diagnostic gene panels.

References

• Molecular Psychiatry • 2024 • Monoallelic loss-of-function variants in GSK3B lead to autism and developmental delay. PMID:39472663
• Unknown • 2022 • Integrative analysis of de novo SNVs and CNVs identifies GSK3B as a candidate neurodevelopmental disorder gene. PMID:35468861

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