Gene dosage disorders (GDDs) are just one example of the rare genetic disorders that modulate gene expression that make up a common collection of risk factors for neuropsychiatric illness. Due to their enormous impact sizes and well-established genetic foundation, GDDs are quickly becoming a popular topic of study. As a result, the genetic-first phenotypic characterization of the same GDD across numerous individuals provides a novel window into genetic impacts on the human brain and behavior, because recurrent GDDs (including aneuploidies and certain copy number variations) are quite common. Though phenotypic profiles may be uniquely connected with a genetic mutation, individual behavioral and neuroimaging features appear nonspecifically impacted by most GDDs, as revealed by the rapidly expanding field of GDD research. To combat this complexity, researchers present a comprehensible survey of genotype-phenotype mappings across various GDDs (with a special emphasis on psychopathology, cognition, and brain anatomy) and an explanation of the methodological and mechanistic origins of the observed convergent and divergent phenotypes. This work produces methodological suggestions for future comparative phenotypic research on GDDs and a set of new testable hypotheses about features of early brain patterning that might influence the complicated mapping of genetic risk onto phenotypic diversity in neuropsychiatric illnesses. A strategy is laid out to better measure phenotypic convergence and divergence across several GDDs and to mechanistically investigate these trends. The answers to the questions raised by GDDs have the potential to significantly advance the taxonomic, neurobiological, and translational understanding of the neuropsychiatric disorder.

Source: jamanetwork.com/journals/jamapsychiatry/article-abstract/2793904