A systems perspective on monoallelic inborn errors of immunity

The genetic architecture of inborn errors of immunity continues to grow in complexity, exposing the limitations of variant-centric concepts that have long shaped the field. While complete loss-of-function genotypes have been instrumental in defining essential gene functions in human immunity and inflammation, they have also entrenched binary interpretations of causality that fail to account for pleiotropy, variable expressivity and incomplete penetrance-especially in monoallelic disease. Monoallelic variants often perturb signaling rather than abolishing it. The integration of these perturbations into molecular and cellular systems, and eventually immune circuits, governs phenotypic expression. Here, we revisit and extend classic concepts of genetic dominance and genetic pleiotropy and suggest that these are not sole properties of alleles but emerge from the complex and dynamic behavior of molecular, cellular and immune systems to buffer genetic variance.