The postsynaptic protein Shank3 (SH3 and multiple ankyrin repeat domains) stands as a notable exception, given that a 50% loss of Shank3 leads to cognitive impairment and possibly neurodegeneration in humans (Grabrucker et al., 2011a, b; Denayer et al., 2012; Phelan and McDermid, 2012; Guilmatre et al., 2014). The gene discussed is SHANK3; the disease is Cognitive impairment.