ASTN2 – Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by impairments in social communication and restricted, repetitive behaviors. Astrotactin-2 (ASTN2) is a neuronal adhesion protein that regulates neuronal migration and synaptic receptor trafficking, making it a compelling candidate for ASD susceptibility. Recent copy number variant (CNV) analyses have implicated heterozygous ASTN2 disruptions as risk factors across ASD cohorts.

Genetic studies have identified rare ASTN2 CNVs in unrelated ASD patients. An array CGH study of five probands from three families reported deletions and duplications spanning intronic and exonic regions of ASTN2 in individuals meeting DSM-5 ASD criteria (PMID:34412080). A large genome-wide CNV screen in 859 ASD cases and replication in 1,336 independent cases demonstrated a significant enrichment of ASTN2 CNVs in ASD versus 1,409 and 1,110 controls (P = 9.5 × 10⁻³) (PMID:19404257). Collectively, these data support a pathogenic role for heterozygous ASTN2 loss or dosage alteration in ASD.

Inheritance of ASTN2 CNVs appears autosomal dominant with variable penetrance; de novo and inherited events have been described. No formal segregation beyond probands has been reported. The variant spectrum comprises deletions spanning exons 6–11, intronic losses (~70 Kb), and duplications including promoter regions, consistent with haploinsufficiency.

Functional models corroborate the genetic association. Patient-derived iPS cells and CRISPR/Cas9 ASTN2–/– neuronal cultures show downregulation of the transcription factor ZNF558 and increased SPATA18 expression and mitophagy activity, linking ASTN2 haploinsufficiency to mitochondrial homeostasis and neuronal survival (PMID:38830862). Astn2 knockout mice exhibit altered exploratory and social behaviors, monoaminergic dysregulation, cortical layer thinning, and reduced dendritic spine density, mirroring ASD-relevant endophenotypes (PMID:36807153).

No conflicting data have refuted the association, although the full penetrance and expressivity of ASTN2 CNVs in ASD remain to be delineated. Additional large-scale sequencing and segregation studies could further clarify variant pathogenicity and recurrence rates.

Taken together, heterozygous ASTN2 CNVs demonstrate moderate clinical validity for ASD through consistent rare variant identification and functional concordance in cellular and animal models. ASTN2 screening may aid in molecular diagnosis of ASD subtypes associated with synaptic and mitochondrial dysfunction.

References

• Psychiatric genetics • 2021 • Rare copy number variants in ASTN2 gene in patients with neurodevelopmental disorders. PMID:34412080
• Nature • 2009 • Autism genome-wide copy number variation reveals ubiquitin and neuronal genes. PMID:19404257
• Translational psychiatry • 2024 • Analysis of human neuronal cells carrying ASTN2 deletion associated with psychiatric disorders. PMID:38830862
• Journal of neurochemistry • 2023 • Astrotactin 2 (ASTN2) regulates emotional and cognitive functions by affecting neuronal morphogenesis and monoaminergic systems. PMID:36807153

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