Aortic stenosis (AS) is a valvular disease characterized by restricted blood flow through the aortic valve and narrowing of the left ventricular outflow tract often leading to left ventricular systolic dysfunction (1). Early onset AS is associated with gene mutations affecting valvulogenesis (2), which can lead to more severe phenotypes and an earlier onset of AS. In Lebanon, consanguinity rates exceed 35% in some areas (3), increasing the likelihood of autosomal recessive mutations (4) that can cause AS. The genetics of familial AS in consanguineous populations Remains poorly characterized. This study aims to identify novel pathologic variants underlying this disease.

This study describes the genetic basis of valvular aortic stenosis in one consanguineous Lebanese family and has identified novel variants in APCDD1, AXIN2, and DVL1, which collectively might explain the phenotype.

Previous studies have linked aortic stenosis to mutations in multiple different genes, most noticeably NOTCH1which was highly correlated with AS given its important role in valvulogenesis and cardiac development (5). Other studies have also identified Lp(a), which is involved in lipid transport, as well as IL6, which is implicated in multiple different inflammatory pathways, as contributors to AS pathogenesis (6, 7), while several others have associated AS to the WNT signaling pathway (8) thus, in addition to valvular calcification and inflammation, alternative pathways involving extracellular matrix remodeling and WNT signaling may contribute to the development AS which emphasizes the genetic heterogeneity of the disease and the need for further research in this field.

In our case, compound heterozygous mutations were detected in APCDD1, AXIN2, and DVL1. Although no variant alone was classified as pathogenic, the presence of heterozygous mutations in APCDD1, AXIN2, and DVL1, all of which are implicated in WNT signaling, suggests a polygenic pathogenesis of AS with a combinatorial inheritance from the parents. In the context of congenital aortic stenosis, the identified missense variants in DVL1, AXIN2, and APCDD1 collectively suggest an intriguing mechanism implicating enhanced WNT signaling activity. Specifically, the missense variant in DVL1 may enhance its affinity toward the Frizzled (Fz) receptor, thereby potentiating WNT pathway activation through stabilized receptor interaction and downstream signaling. Concurrently, the variant identified in AXIN2 potentially reduces its affinity for β-catenin, impairing the effective assembly of the β-catenin degradation complex. This decreased affinity can result in elevated cytoplasmic β-catenin levels, facilitating nuclear translocation and enhanced transcription of WNT-responsive genes involved in valvular interstitial cell proliferation and matrix remodeling. Similarly, the missense variant in APCDD1 may result in reduced affinity toward LRP5/6 co-receptors, diminishing its inhibitory capacity on WNT signaling (Figure 2). Collectively, these subtle molecular alterations—enhanced DVL1-Fz interaction, diminished AXIN2–β-catenin interaction, and attenuated APCDD1–LRP5/6 binding—could synergistically amplify canonical WNT signaling. Such a mechanism aligns well with documented evidence that dysregulated WNT signaling contributes to pathological valve thickening, fibrosis, and calcification—hallmarks of aortic stenosis (9).

These findings emphasize the delicate balance within the WNT signaling pathway critical for normal aortic valve formation and underscore how slight functional changes in pathway components can collectively predispose individuals to congenital valve malformations, including aortic stenosis.

These results support the developing pattern of polygenic inheritance patterns in congenital heart diseases (CHD)where different variants within the same functional pathway act synergistically and increase disease risk (10). This becomes especially relevant in consanguineous populations where deleterious mutations become more apparent and may be at an increased risk of developing CHD.

Uncovering the genetic variants of AS has major potential in the field of precision medicine, especially in high-risk groups, including consanguineous families despite the very limited outcomes for the autosomal recessive pattern postulate. Genetic screening could provide early diagnosis of AS and enable the development of specific personalized therapies.

Our study provides insights into the genetic basis of AS through whole exome sequencing allowing for fast and accurate variant identification. Furthermore, this study adds to the limited research and literature on the genetic variants of valvular aortic stenosis. However, the small sample size (a single affected patient analyzed with her parents) limits the generalizability of the results. No other consanguineous families with AS or unrelated controls were included, so the proposed contribution of WNT pathway variants to this patient's phenotype remains speculative. Future studies involving larger cohorts and functional analyses are planned to validate these preliminary findings. Additionally, undetected genetic or epigenetic changes may influence disease severity, as our study did not investigate non-coding regions of the DNA.

This study broadens the genetic outlook of AS by confirming the WNT pathway through combinatorial interaction as a major player in congenital heart diseases. These findings point out the complexity of AS genetics, the interplay of multiple different genetic pathways in its pathology, and the need for continued research into its genetic basis. Future studies involving additional patients are warranted to validate these WNT-related genetic findings and confirm their contribution to AS pathogenesis.