Importance: Rare genetic disorders modulating gene expression-as exemplified by gene dosage disorders (GDDs)-represent a collectively common set of high-risk factors for neuropsychiatric illness. Research on GDDs is rapidly expanding because these variants have high effect sizes and a known genetic basis. Moreover, the prevalence of recurrent GDDs (encompassing aneuploidies and certain copy number variations) enables genetic-first phenotypic characterization of the same GDD across multiple individuals, thereby offering a unique window into genetic influences on the human brain and behavior. However, the rapid growth of GDD research has unveiled perplexing phenotypic convergences and divergences across genomic loci; while phenotypic profiles may be specifically associated with a genomic variant, individual behavioral and neuroimaging traits appear to be nonspecifically influenced by most GDDs.
Observations: This complexity is addressed by (1) providing an accessible survey of genotype-phenotype mappings across different GDDs, focusing on psychopathology, cognition, and brain anatomy, and (2) detailing both methodological and mechanistic sources for observed phenotypic convergences and divergences. This effort yields methodological recommendations for future comparative phenotypic research on GDDs as well as a set of new testable hypotheses regarding aspects of early brain patterning that might govern the complex mapping of genetic risk onto phenotypic variation in neuropsychiatric disorders.
Conclusions and relevance: A roadmap is provided to boost accurate measurement and mechanistic interrogation of phenotypic convergence and divergence across multiple GDDs. Pursuing the questions posed by GDDs could substantially improve our taxonomical, neurobiological, and translational understanding of neuropsychiatric illness.