Fig. 2

Threshold determines penetrance. We use a hypothetical case to illustrate the conceptual relationship between threshold and penetrance. Consider a hypomorphic allele m of a gene X. The X-axis is the level or activity of X. The Y-axis is the number of individuals with a particular [X]. Due to many factors, the [X] displays a distribution curve. A hypothetical threshold for [X] is drawn. If [X] falls below the threshold, the individual will exhibit the clinical phenotype. If [X] is above the threshold, the individuals will be phenotypically normal. In this hypothetical example, the m variant is recessive, because all m/ + individuals will be above threshold. The m variant is incompletely penetrant, because only a fraction of m/m individuals will be below threshold and exhibit phenotypes. If the threshold shifts to the right, the penetrance will become higher, i.e., more individuals are below threshold. If the threshold shifts to the left, then less individuals are below threshold, hence a lower penetrance