Abstract
INTRODUCTION: Aortic stenosis (AS) is a common valvular disease with a complex and incompletely defined genetic architecture. The contribution of inherited factors may be particularly prominent in consanguineous populations, where familial clustering suggests a strong hereditary component. We investigated the genetic basis of AS in a consanguineous Lebanese family. METHODS: We performed clinical phenotyping and trio whole-exome sequencing (WES) on a 12-year-old female proband with severe valvular AS and her phenotypically normal consanguineous parents. Variants were assessed with standard filtering for rarity, predicted functional impact, and biological plausibility, with particular attention to genes implicated in cardiovascular development and signaling pathways. RESULTS: The proband presented with severe aortic stenosis, bicuspid aortic valve, dilated aortic root and ascending aorta, and mild -moderate tricuspid regurgitation, requiring multiple interventions (balloon valvuloplasty, Ross procedure, and right ventricle-pulmonary artery conduit replacement). WES identified three heterozygous variants in genes belonging to the Wnt signaling pathway APCDD1, DVL1, and AXIN2 in the proband, which were inherited from the normal parents. DISCUSSION: The co-occurrence of heterozygous variants in Wnt pathway genes in a child with severe AS highlights a potential polygenic or pathway-level contribution to disease susceptibility, even within a consanguineous context. These findings support a role for Wnt signaling in aortic valve development and pathology, motivating further functional studies and broader cohort analyses to clarify pathogenicity, segregation, and clinical relevance.