Relevance to Autism

Rare variants and deletions have been identified in AUTS2 in individuals with ASD and other neurodevelopmental disorders (NDD) in multiple studies. While initial studies were performed without rigorous comparison with controls, Beunders et al., 2013 demonstrated a statistical enrichment of exonic AUTS2 deletions in NDD cases compared to controls (24/49,684 cases vs. 0/16,784 controls; P=0.00092). In addition to ASD, there is genetic evidence implicating it in developmental delay/intellectual disability, epilepsy and ADHD. Knockdown of AUTS2 in zebrafish resulted in smaller head size, neuronal reduction, and decreased mobility (Oksenberg et al., 2013), while knockdown in mice led to impaired cortical neuronal migration and neuritogenesis (Hori et al., 2014). A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified AUTS2 as a gene reaching exome-wide significance (P < 2.5E-06); association of AUTS2 with ASD risk in this analysis was found to be driven both by de novo variants (in particular, de novo loss-of-function variants in six ASD probands from the SPARK cohort) and rare inherited loss-of-function variants transmitted from unaffected parents to affected offspring. Erdogan et al., 2025 further delineated a neurodevelopmental phentoype associated with variants in the HX repeat domain of AUTS2 that was distinct from the phenotype associated with AUTS2 haploinsufficency; the phenotype described in individuals with missense or in-frame variants in the HX repeat domain more closely resembled that in individuals with Rubinstein-Taybi syndrome and was characterized by severe intellectual disability, distinct craniofacial and skeletal dysmorphic findings, and neuroimaging findings.

Molecular Function

Component of a Polycomb group (PcG) multiprotein PRC1-like complex, a complex class required to maintain the transcriptionally repressive state of many genes, including Hox genes, throughout development.In the cytoplasm, plays a role in axon and dendrite elongation and in neuronal migration during embryonic brain development. Promotes reorganization of the actin cytoskeleton, lamellipodia formation and neurite elongation via its interaction with RAC guanine nucleotide exchange factors, which then leads to the activation of RAC1.

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Model Summary

Suppression of auts2 in zebrafish embryos caused microcephaly that could be rescued by either the full-length or the short C-terminal isoform of AUTS2.

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