An exploratory genomic landscape of unicuspid aortic valve

Abstract Unicuspid aortic valve (UAV) is a rare congenital malformation with severe clinical consequences, and its genetic background remains poorly defined. We present an exploratory genomic resource for UAV, generated from whole-exome sequencing (WES) of nine families (including probands and 19 unaffected relatives) and integrated with single-cell RNA sequencing (scRNA-seq) data from human embryonic hearts. The scRNA-seq dataset enabled the identification of genes expressed in valve-forming cell populations during development, providing a biologically informed filter for candidate variant prioritisation. Further prioritisation identified 81 candidate variants across 68 genes with enrichment in extracellular matrix (ECM) organisation and developmental signalling pathways, particularly transforming growth factor-β-mediated signalling. Complementary exome-wide family segregation analysis further supported this pattern, again highlighting ECM organisation and developmental signalling as recurrently enriched biological themes. By establishing a preliminary genomic dataset, this study provides a resource for further validation, expansion to larger cohorts, and exploration of the molecular architecture underlying this rare disorder.