Genetic Determinants of Wound Healing: Monogenic Disorders and Polygenic Influence

Abstract

Highlights: What are the main findings? Monogenic and polygenic disorders—despite differing genetic architectures—converge on shared downstream failures in hemostasis, inflammation, cellular proliferation, and extracellular matrix remodeling. Monogenic conditions provide direct mechanistic insight into how discrete pathway defects impair repair, whereas polygenic diseases reveal how cumulative genetic risk and metabolic stressors overwhelm tissue regenerative capacity. What are the implications of the main finding? Recognizing the continuum between single-gene disruptions and multifactorial genetic susceptibility enables a more mechanistically driven classification of impaired wound healing. By synthesizing both preclinical mechanistic studies and clinical outcome data across monogenic and polygenic conditions, this review offers a comprehensive resource for understanding genetic influences on real-world wound healing outcomes. (1) Background: Wound healing is a highly coordinated process encompassing hemostasis, inflammation, angiogenesis, keratinocyte migration, collagen deposition, and extracellular matrix remodeling. Successful repair also requires adequate nutrient and oxygen delivery through a well-developed vascular supply. Disruption of these processes can occur through aberrations in diverse biological pathways, including extracellular matrix organization, cellular adhesions, angiogenesis, and immune regulation. (2) Methods: We reviewed mechanisms of impaired tissue repair in monogenic disorders by focusing on three categories—connective tissue, hematological/immunological, and aging-related disorders—to illustrate how single-gene defects disrupt inflammation, cellular proliferation, and matrix remodeling. Additionally, we reviewed various polygenic disorders—chronic kidney disease, diabetes mellitus, hypertension, and obesity—to contrast complex multifactorial pathologies with single-gene defects. (3) Results: This review establishes that genetic impediments, despite their distinct etiologies, monogenic and polygenic disorders share critical downstream failures in the wound healing cascade. While monogenic diseases illustrate direct causal links between specific protein deficits and repair failure, polygenic diseases demonstrate how multifactorial stressors overwhelm the body’s regenerative capacity. (4) Conclusions: This review synthesizes current evidence on both monogenic diseases and polygenic contributions to impaired wound healing. These findings highlight that genetic susceptibility is a decisive factor in the ability to restore tissue homeostasis. This underscores the profound impact of genetic background on the efficacy of hemostasis, inflammation, and remodeling.