Incomplete penetrance in primary immunodeficiency: a skeleton in the closet

Abstract

Primary immunodeficiencies (PIDs) comprise a diverse group of over 400 genetic disorders that result in clinically apparent immune dysfunction. Although PIDs are classically considered as Mendelian disorders with complete penetrance, we now understand that absent or partial clinical disease is often noted in individuals harboring disease-causing genotypes. Despite the frequency of incomplete penetrance in PID, no conceptual framework exists to categorize and explain these occurrences. Here, by reviewing decades of reports on incomplete penetrance in PID we identify four recurrent themes of incomplete penetrance, namely genotype quality, (epi)genetic modification, environmental influence, and mosaicism. For each of these principles, we review what is known, underscore what remains unknown, and propose future experimental approaches to fill the gaps in our understanding. Although the content herein relates specifically to inborn errors of immunity, the concepts are generalizable across genetic diseases.

Keywords: Human genetics; Mosaicism; Penetrance; Primary immunodeficiency; Variable expressivity.

Figure 1.. Four principles of incomplete penetrance in primary immunodeficiency.

Inner circle represents the four broad principles of incomplete penetrance, with the outer circle denoting specific processes that are established (dark) or hypothesized (light) to contribute.