AUTS2-related Syndrome: Insights from a large European cohort.

Purpose: AUTS2-related syndrome is a condition characterized by developmental delay, autism spectrum disorder, and intellectual disability. From alternative promoters AUTS2 encodes two distinct long and short isoforms encoding a putative transcriptional activator.
Methods: Through a European collaborative study, we collected clinical and genotype data on the largest AUTS2- related syndrome cohort of 58 patients harboring genomic rearrangements or single nucleotide variants (SNVs).
Results: Pathogenic SNVs were recurrently found in individuals from different countries, suggesting mutational hotspots. Independent from the underlying defect at the AUTS2 locus, we observed that autistic behavior, hyperactivity, learning difficulties and speech delay are common features of AUTS2- related syndrome. Among patients with SNVs, individuals carrying pathogenic variants affecting both the longer and the shorter AUTS2 transcripts showed a recognizable phenotype with microcephaly, brachycephaly, micro-retrognathia, broad nasal base and anteverted nares. Behavioral disorders were statistically more common in patients with variants affecting only the longer isoform. Arthrogryposis and stiff movements were only noticed in patients with SNVs.
Conclusion: This study provides a comprehensive clinical characterization of AUTS2- related syndrome, unravels few genotype-phenotype correlations and it suggests that disruption of the two distinct AUTS2 transcripts has a different impact on clinical phenotype.
(Copyright © 2025. Published by Elsevier Inc.)