A systems perspective on monoallelic inborn errors of immunity.

Monoallelic variants in inborn errors of immunity often perturb signaling pathways rather than abolish gene function, highlighting complex system-level influences on disease expression.

• Why it matters: Understanding the limitations of variant-centric models is crucial because they overlook pleiotropy, variable expressivity, and incomplete penetrance in monoallelic diseases, impeding accurate diagnosis and treatment.
• What they did: The authors review and extend concepts of genetic dominance and pleiotropy, emphasizing how molecular, cellular, and immune system dynamics buffer genetic variance and influence phenotypic outcomes.
• The result: This systems perspective suggests that genetic effects emerge from complex immune circuit behaviors, offering a more nuanced framework for interpreting monoallelic inborn errors of immunity.