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.

中文翻译：

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罕见遗传病对脑表型的趋同和分化：综述。

重要性 调节基因表达的罕见遗传病——以基因剂量障碍 (GDD) 为例——代表了一组共同​​的神经精神疾病高危因素。对 GDD 的研究正在迅速扩展，因为这些变体具有高效应量和已知的遗传基础。此外，复发性 GDD（包括非整倍体和某些拷贝数变异）的普遍存在使得能够对多个个体的相同 GDD 进行遗传优先表型表征，从而为了解遗传对人类大脑和行为的影响提供了一个独特的窗口。然而，GDD 研究的快速发展揭示了基因组位点之间令人困惑的表型趋同和差异；虽然表型特征可能与基因组变异特别相关，个体行为和神经影像学特征似乎受到大多数 GDD 的非特异性影响。观察 这种复杂性通过以下方式解决：(1) 提供跨不同 GDD 的基因型-表型映射的可访问调查，重点是精神病理学、认知和大脑解剖学，以及 (2) 详细说明观察到的表型收敛和发散的方法和机制来源。这项工作为未来 GDD 比较表型研究提供了方法学建议，并提出了一组关于早期大脑模式方面的新的可测试假设，这些方面可能控制遗传风险到神经精神疾病表型变异的复杂映射。结论和相关性 提供了路线图，以促进跨多个 GDD 的表型收敛和发散的准确测量和机制询问。追寻 GDD 提出的问题可以大大提高我们对神经精神疾病的分类学、神经生物学和转化学理解。