Secondly, the bidirectional mechanism offers a more nuanced interpretation of conventional models of genetic susceptibility to disease or drug response because risk-carrying variants located within genes at the extremes of composition (for example, SHANK3 for autism spectrum disorder or APOE or ABCA7 for Alzheimer’s disease) will be subject to reduced or increased impact (expressivity/penetrance) according to the direction of profile perturbation. The gene discussed is SHANK3; the disease is early-onset autosomal dominant Alzheimer disease.