Non-coding structural variants disrupt FOXG1 transcriptional regulation in early neurodevelopment

Non-coding structural variants downstream of FOXG1, disruption of a ~124 kb critical regulatory region containing neurodevelopmental enhancers

Two non-coding structural variants downstream of FOXG1 are identified in individuals with FOXG1 syndrome-like features, delimiting a critical regulatory region of approximately 124 kb. Epigenomic profiling (ATAC-seq, H3K27ac ChIP-seq) and in vivo enhancer assays (zebrafish) characterize and validate multiple regulatory elements within this region. These findings explain the pathogenic mechanism of FOXG1 non-coding SVs and provide precise landmarks for diagnostic interpretation.

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Elucidation of the FOXG1 regulatory region is clinically relevant because non-coding SVs are invisible by exome and standard panels — only WGS or high-resolution CMA can detect them. This work provides precise coordinates for annotating these variants in routine practice and reducing diagnostic odyssey in FOXG1 syndromes without coding variants.

Clinical impact: 2/3 · Evidence strength: 2/3 · Novelty: 2/2 · Sample size: 0/1 · Publication status: 1/1 → Total: 7/10