Trisomy rescues and mosaic chromosomal alterations in autism spectrum disorder

Trisomy rescue, a process in which somatic cell divisions correct zygotic trisomies by discarding an extra chromosome, can generate mosaic chromosomal abnormalities with profound consequences for neurodevelopment. Although this mechanism is well recognized in developmental biology, its role in autism spectrum disorder (ASD) and related neurodevelopmental disorders (NDDs) has not been systematically explored. Prior microarray-based studies quantified rates of chromosomal abnormalities (ChAs) in ASD/NDD cohorts, but these approaches do not allow detection of triosomy rescues.

Leveraging newly assembled whole-genome sequencing (WGS) and ATAC-seq datasets spanning thousands of ASD/NDD donors, Peter Park and colleagues aim to comprehensively identify trisomy rescue events, map their genomic breakpoints and assess their impact on gene regulation and chromatin state. Their recent analysis of Autism BrainNet donors revealed a previously unrecognized trisomy rescue pattern that produced complex ChAs, highlighting the need for broader investigation. By applying their algorithms across large-scale biobanks, they will quantify the prevalence and consequences of trisomy rescues in ASD/NDDs and benchmark them against neurotypical populations. This work will establish trisomy rescue as a key mechanism shaping somatic genomic mosaicism and neurodevelopmental disease risk.