Transcriptional and Splicing Dysregulation in CHARGE Syndrome Mouse Models Explains the Cerebellar Developmental Defects

CHARGE syndrome (CS) is a rare genetic disorder characterized by a complex pattern of congenital malformations. One poorly understood hallmark of CS is intellectual disability related to autism spectrum disorder (ASD). Pathogenic variants in CHD7, a chromatin remodeler, are the main cause of CS, while ARB2A, a co-transcriptional regulator, has also been reported as another cause of CS. Both encoded proteins play crucial roles in transcriptional regulation and alternative splicing, which dysregulation likely contributes to all aspects of CS pathogenesis. This project is specifically focused on the neurobiological deficits. Using Arb2a^Tp/Tp and Chd7^Gt/+ mouse models, we previously found common behavioral abnormalities including hyperactivity and social deficits, which are associated with cerebellar malformations, particularly in lobules XI/X of the vermis. Histological analyses further revealed ectopic localization of granule cells and Purkinje cells, suggesting disrupted neuronal migration. To investigate the underlying molecular mechanism, we have now carefully analyzed the transcriptome of granule vs. non-granule cells that were isolated from postnatal day 7 (P7) cerebella of wild-type and mutant mice. Bulk RNA sequencing followed by differential expression and splicing analyses (DESeq2, rMATS) revealed widespread dysregulation of genes involved in cerebellar development, synaptogenesis, and neurotransmission. Several key regulators of pre- and post-synaptic signaling were commonly affected across both models, indicating convergent molecular dysfunction. Overall, these findings provide new mechanistic insights into how CHD7 and ARB2A mutations disrupt cerebellar gene expression programs, thereby contributing to the neurodevelopmental and behavioral manifestations of CHARGE syndrome.