Incomplete penetrance in inborn errors of immunity: A skeleton in the closet—The sequel

Primary immunodeficiencies (PIDs), more recently renamed inborn errors of immunity (IEIs), are a diverse group of over 550 genetic disorders. They cause clinically apparent immune dysregulation, leading to infections, autoinflammation, autoimmunity, and cancer. Initially, most IEIs were described as Mendelian disorders with complete penetrance, but the community has now shown that, in most IEIs, some individuals harboring disease-causing genotypes display only partial clinical disease, or no disease at all. Thus, most IEIs are actually Mendelian disorders with incomplete penetrance. Despite the frequency of incomplete penetrance in IEIs, the conceptual framework for systematically categorizing and explaining these occurrences remains limited. Here, I expand on four recurrent themes of incomplete penetrance that we have recently proposed: genetic variant quality, epigenetic and genetic modification, environment, and mosaicism. For each of these principles, I review what is known and unknown and propose future experimental approaches to fill the gaps in our knowledge. I focus on IEIs, but these concepts can be generalized to all genetic diseases.