STXBP1 – Autism Spectrum Disorder

STXBP1 has been implicated in autism spectrum disorder through the identification of rare heterozygous variants in unrelated individuals. In a Chinese ASD cohort of 1,543 probands, one de novo likely gene-disruptive STXBP1 mutation was observed (PMID:27824329), corresponding to approximately 0.06% of patients. Separately, targeted resequencing of 35 synaptic genes in 61 patients with co-occurring macrocephaly and autism-epilepsy phenotype revealed a rare predicted deleterious STXBP1 variant c.*77C>T in one patient (PMID:26537360). No familial segregation data were reported.

Functional assays and cellular models consistently demonstrate that Munc18-1 (encoded by STXBP1) is essential for synaptic vesicle docking, priming, and neurotransmitter release. Conditional heterozygous loss of STXBP1 in human neurons lowers Munc18-1 and syntaxin-1 levels by ~30% and reduces evoked and spontaneous neurotransmission by ~50%, mirroring synaptic deficits observed in ASD (PMID:26280581). These mechanistic studies support a haploinsufficiency model but lack direct replication in ASD-specific in vivo models.

Key Take-home: STXBP1 heterozygous de novo variants are observed in rare ASD cases, highlighting the need for further genetic and functional validation before routine clinical testing.

References

• Neuromolecular medicine | 2016 | Targeted Gene Resequencing (Astrochip) to Explore the Tripartite Synapse in Autism-Epilepsy Phenotype with Macrocephaly. PMID:26537360
• Nature communications | 2016 | De novo genic mutations among a Chinese autism spectrum disorder cohort. PMID:27824329
• The Journal of clinical investigation | 2015 | Analysis of conditional heterozygous STXBP1 mutations in human neurons. PMID:26280581

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