In the meantime, comparative studies are needed to understand the shared and distinct phenotypic effects of rare large-effect alleles in humans and model systems. To some extent, the phenotypes of psychiatric disease must represent the common outcome of multiple different pathways at the level of brain systems that underlie their shared behavioral and cognitive phenotypes (29, 62). Decades of research have identified ASD in multiple rare genetic syndromes with specific constellations of multi-organ phenotypes, including Timothy syndrome, tuberous sclerosis, Potocki-Lupski syndrome, cortical dysplasia focal epilepsy syndrome, and fragile X syndrome. New syndromes identified via WES are no different, suggesting that the phenotypic complexity of ASD may in part be explained by the effects of different rare major-effect-size alleles (66). Such inverse mapping or genotype-first approaches are at early stages in SCZ and BPD (48). Additionally, it is not known what genetic or environmental factors influence the diversity of clinical outcomes in people harboring most of the major-effect loci. Understanding the mechanisms of such variable expressivity will undoubtedly provide critical pathophysiological clues.
