Inhibiting SOX18 with propranolol restores vascular integrity in NR2F2-driven malformations

Genomics has advanced our ability to identify disease-causing mutations, but translating this information into treatments remains challenging, particularly for rare genetic diseases. Key challenges remain, including understanding how variants of unknown significance (VUS) disrupt molecular and cellular function and how to treat perturbed physiology. Here, we identify a de novo heterozygous mutation in the NR2F2 gene, a regulator of venous endothelial cell identity, which causes an orphan paediatric syndrome, characterized by leaky, aberrant vascular development. Functional validation in human embryonic stem cells carrying the proband’s mutation uncovers venous differentiation defects. NR2F2 is a nuclear receptor that can form dimers and recruits other transcription factors to modulate the venous gene expression program. Through in silico modelling and live-cell molecular imaging, we demonstrate that the NR2F2 variant protein is hypermobile, unable to form homodimers, and fails to recruit a critical partner, SOX18, thereby disrupting the venous transcriptional program. Multi-omics analysis further identifies an opposing yet coordinated regulation of common target genes by SOX18 and NR2F2 in venous endothelial cells. Here, we posit that inhibiting SOX18 activity may mitigate NR2F2 dysfunction. Remarkably, SOX18 pharmacological blockade shows a rescues NR2F2 loss-of-function in hESC-derived venous endothelial cells. Treatment with an FDA-approved drug known for its off-target SOX18 inhibition led to significant reduction in haemorrhaging resulting in a significant increase in quality of life. This proof of concept identifies a postnatal therapeutic window, coinciding with vascular plasticity during organ maturation that can be leveraged to manage vascular anomalies through successful drug repurposing.