Monogenic Diseases: A View Through the Landscape–Attractor Framework

Monogenic diseases are traditionally interpreted through a linear causal model linking pathogenic variants to molecular dysfunction and clinical phenotypes. However, this model does not fully explain incomplete penetrance, variable expressivity, and heterogeneous disease progression. This review aims to explore the applicability of the landscape–attractor framework, originally developed in evolutionary and developmental biology and subsequently extended to gene regulatory networks, to the interpretation of monogenic diseases. We propose that pathogenic variants act as persistent perturbations of interconnected molecular networks, modifying the stability and accessibility of physiological and pathological states. Within this framework, phenotypic variability emerges from interactions between the causal variant and genetic modifiers, epigenetic regulation, environmental influences, stochastic processes, and compensatory mechanisms. We further extend this perspective across molecular, cellular, tissue, and organismal levels, introducing the concept of functional fitness to describe disease-related physiological performance. Finally, we discuss how therapeutic interventions may redirect biological systems toward more favorable functional states without necessarily correcting the underlying genetic defect. This framework offers a complementary systems-level perspective on genotype–phenotype relationships and suggests experimentally testable hypotheses for understanding and modifying disease expression.