Multiomic Analyses Identifies Novel Risk Genes and Spatiotemporal Pathogenic Gene Clusters for Congenital Ventriculomegaly

Introduction: Congenital cerebral ventriculomegaly (CCV) is the most common prenatal brain abnormality with congenital hydrocephalus being the most frequent indication for pediatric neurosurgical intervention. While the pathology of CCV is often attributed to a primary accumulation of CSF, whole exome sequencing studies have suggested that many cases of CCV may be due to genetic variations leading to aberrant neurodevelopment, with CCV often being associated with neurodevelopmental delay disorders (NDD).

Methods: In the largest cohort of its kind, we analyzed the exomes of 2,697 CCV patient-parent trios alongside 1,798 control trio exomes to identify CCV risk genes. We then integrated genomic results with single-cell and spatial transcriptomic data and natural language processing-derived data from CCV patient medical records.

Results: Whole exome sequencing identified 35 genes harboring damaging, de novo variants (DNVs) that reached the threshold for genome-wide significance, along with 98 high-pLI genes with multiple damaging DNVs. Comparison of these CCV risk genes against DisGeNET-curated disease gene lists demonstrated strong overlap with NDD-associated genes. Spatiotemporal transcriptomic analysis identified distinct gene expression clusters, with many CCV risk gene-gene correlations conserved between single-cell and spatial transcriptomic data that demonstrated high activity in neuronal and neural progenitor cell types in periventricular regions. Phenotypic analysis using artificial intelligence revealed distinct clinical profiles among proband gene clusters.

Conclusion : These analyses suggest that beyond the mechanical accumulation of CSF, a genetic disruption of cellular development underlies the pathogenesis of CVV and its link to NDD. Furthermore, the relationship between genetic mutations and phenotypic profiles of CVV patients supports the utility of genetic testing to guide patient management and the use of CVV as a prenatal sonographic risk factor for NDD.