Non-coding structural variants identify a commonly affected regulatory region steering FOXG1 transcription in early neurodevelopment [CUT&Run]

Pathogenic FOXG1 variants cause FOXG1 syndrome. Although structural variants (SVs) in the non-coding region downstream of FOXG1 have been reported in 38 individuals with similar characteristics, the regulatory pathomechanisms remain unknown.

We identified a de novo non-coding deletion in an individual with FOXG1 syndrome-like disorder, allowing us to delineate a ~124 kb commonly affected regulatory region (CARR). By integrating epigenomics data, 3D chromatin interaction profiles (Hi-C, UMI-4C), and in vivo enhancer assays in zebrafish, we uncovered multiple regulatory elements within this CARR, including a neuronal enhancer cluster and a conserved boundary of the FOXG1-containing topologically associating domain (TAD).