Understanding rare genetic brain disorders with overlapping neurological and psychiatric phenotypes is of increasing importance given the potential for developing disease models that could help to understand more common, polygenic disorders. However, the traditional clinical boundaries between neurology and psychiatry result in frequent segregation of these disorders into distinct silos, limiting cross-specialty understanding that could facilitate clinical and biological advances. In this Review, we highlight multiple genetic brain disorders in which neurological and psychiatric phenotypes are observed, but for which in-depth, cross-spectrum clinical phenotyping is rarely undertaken. We describe the combined phenotypes observed in association with genetic variants linked to epilepsy, dystonia, autism spectrum disorder and schizophrenia. We also consider common underlying mechanisms that centre on synaptic plasticity, including changes to synaptic and neuronal structure, calcium handling and the balance of excitatory and inhibitory neuronal activity. Further investigation is needed to better define and replicate these phenotypes in larger cohorts, which would help to gain greater understanding of the pathophysiological mechanisms and identify common therapeutic targets.

鉴于开发有助于理解更常见的多基因疾病的疾病模型的潜力，了解具有重叠的神经和精神表型的罕见遗传性脑部疾病变得越来越重要。然而，神经病学和精神病学之间的传统临床界限导致这些疾病经常被分成不同的孤岛，限制了可以促进临床和生物学进步的跨专业理解。在这篇综述中，我们重点介绍了多种遗传性脑部疾病，其中观察到神经和精神表型，但很少对其进行深入的跨谱临床表型分析。我们描述了观察到的与癫痫、肌张力障碍、自闭症谱系障碍和精神分裂症相关的遗传变异相关的组合表型。我们还考虑了以突触可塑性为中心的常见潜在机制，包括突触和神经元结构的变化、钙处理以及兴奋性和抑制性神经元活动的平衡。需要进一步的研究来更好地定义和在更大的队列中复制这些表型，这将有助于更好地了解病理生理机制并确定常见的治疗靶点。