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ASTN2 – Intellectual Disability

Rare heterozygous copy-number variants (CNVs) affecting ASTN2 have been identified in patients with intellectual disability (ID), supporting an autosomal dominant contribution to disease. In a cohort of 5,531 well-phenotyped ID/multiple congenital anomalies patients, a de novo single-gene ASTN2 CNV was detected among 1,388 carriers of rare CNVs ([PMID:24038936]). In a separate study of neurodevelopmental disorder cohorts, three unrelated families totaling five probands harbored rare intronic and exonic CNVs in ASTN2, including a 70 Kb intron 19 deletion and a 205 Kb exons 6–11 deletion, with associated intellectual disability in several affected members ([PMID:34412080]). No multi-generation segregation has been reported.

Functional studies provide moderate support for ASTN2’s role in neuronal development. Patient-derived and CRISPR-edited iPSC-derived neurons with heterozygous or homozygous ASTN2 deletion show downregulation of the forebrain progenitor gene ZNF558, upregulation of SPATA18, and increased mitophagy activity, linking ASTN2 loss to mitochondrial and synaptic dysfunction ([PMID:38830862]). In Astn2 knockout mice, CRISPR/Cas9-mediated deletion causes thinning of hippocampal and cortical layers, reduced dendritic spine density and PSD95 expression, altered striatal dopamine and serotonin turnover, and cognitive and behavioral abnormalities resembling human ID phenotypes ([PMID:36807153]).

References

  • Human Mutation • 2013 • Clinical significance of de novo and inherited copy-number variation. PMID:24038936
  • Psychiatric Genetics • 2021 • Rare copy number variants in ASTN2 gene in patients with neurodevelopmental disorders. PMID:34412080
  • 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

Evidence Based Scoring (AI generated)

Gene–Disease Association

Limited

6 unrelated probands with heterozygous de novo or inherited ASTN2 CNVs in intellectual disability cohorts ([PMID:24038936]; [PMID:34412080]), no segregation data

Genetic Evidence

Limited

6 probands with rare heterozygous CNVs impacting ASTN2, no multi-generation segregation

Functional Evidence

Moderate

iPSC and knockout mouse models demonstrate neuronal migration, synaptic and mitophagy defects consistent with intellectual disability phenotypes