(223) Identification of Gene Variants in Fibrosis-Associated Pathways as Strong Candidate Drivers of Peyronie’s Disease Pathogenesis

Introduction Peyronie’s disease (PD) is a localized, benign fibrotic disorder of the penile tunica albuginea, typified by plaque formation and compromised erectile function. Despite extensive clinical recognition, its genetic architecture and molecular pathogenesis remain largely unresolved. Conventional experimental paradigms, predominantly relying on pharmacologically induced fibrosis in non-human models, fail to recapitulate systemic, heritable, or patient-specific determinants of disease. Objective In this study, we interrogate both germline and somatic genomic variants to delineate the molecular networks orchestrating fibrotic remodeling, with the goal of identifying foundational drivers of PD. Methods We performed whole exome sequencing (WES) on peripheral blood DNA from 36 sporadic Peyronie’s disease (PD) patients and 16 relatives across eight familial PD pedigrees. To ensure specificity, all participants with comorbid conditions or disorders potentially linked to PD were systematically excluded, isolating pure PD cases for analysis. In patients undergoing surgical intervention, WES was extended to DNA from fibrotic plaques and adjacent normal tunica albuginea, enabling ultra-deep coverage (>500×) for high-resolution discrimination between germline and tissue-specific somatic variants. Functional enrichment and pathway analyses were conducted using g: Profiler2 (v0.2.1), informing the development of our precision-oriented diagnostic gene panel. Results Our analytical approach, encompassing over 150 genes, revealed an average of >20 functionally significant variants per patient from a total of >1,000 detected variants. These variants were profoundly enriched in fibrosis-associated pathways (p < 4.12E-105). In familial PD, deleterious variants in NOS3, LAMB2 and LAMA5 emerged as key candidates, whereas isolated PD implicated 12 genes, including COL4A1, COL4A2, COL5A1, COL6A3, PLOD1, ELN, MMP14, TGFB1I1, TGFB2, PDE3B, ITGB1, and NOS2. These genes converge on extracellular matrix organization, collagen and elastin remodeling, integrin signaling, nitric oxide synthase activity, and fibrosis regulation-mechanisms central to PD pathobiology. All reported variants are novel within the context of PD. Conclusions Peyronie’s disease demonstrates profound genetic heterogeneity, reflecting complex, multi-layered molecular networks rather than a singular, localized lesion. The variants we identified illuminate the mechanisms underlying disease onset, progression, and variability in therapeutic response. Importantly, these findings provide a molecular explanation for why uniform treatments yield divergent outcomes across patients. By reframing PD as a genetically orchestrated fibrotic disorder, our work lays the groundwork for precision medicine, enabling the development of targeted, individualized therapies tailored to each patient’s unique genetic and molecular profile. Disclosure No