Department of Developmental Biology, Washington University School of Medicine, Saint Louis, MO, 63110, USA.
Stem Cell Rev Rep. 2023 Apr;19(3):639-650. doi: 10.1007/s12015-022-10475-0. Epub 2022 Nov 12.
Copy number variants (CNVs), involving duplication or deletion of susceptible intervals of the human genome, underlie a range of neurodevelopmental and neuropsychiatric disorders. As accessible in vivo animal models of these disorders often cannot be generated, induced pluripotent stem cell (iPSC) models derived from patients carrying these CNVs can reveal alterations of brain development and neuronal function that contribute to these disorders. CNVs involving deletion versus duplication of a particular genomic interval often result both in distinct clinical phenotypes and in differential phenotypic penetrance. This review initially focuses on CNVs at 15q13.3, which contribute to autism spectrum disorder, attention deficit/hyperactivity disorder, and schizophrenia. Like most CNVs, deletions at 15q13.3 usually cause severe clinical phenotypes, while duplications instead result in highly variable penetrance, with some carriers exhibiting no clinical phenotype. Here, we describe cellular and molecular phenotypes seen in iPSC-derived neuronal models of 15q13.3 duplication and deletion, which may contribute both to the differential clinical consequences and phenotypic penetrance. We then relate this work to many other CNVs involving both duplication and deletion, summarizing findings from iPSC studies and their relationship to clinical phenotype. Together, this work highlights how CNVs involving duplication versus deletion can differentially alter neural development and function to contribute to neuropsychiatric disorders. iPSC-derived neuronal models of these disorders can be used both to understand the underlying neurodevelopmental alterations and to develop pharmacological or molecular approaches for phenotypic rescue that may suggest leads for patient intervention. Top: Deletion versus duplication of the same genomic interval results in different clinical phenotypes and degrees of phenotypic penetrance. Example findings schematized. Bottom: iPSC-derived neurons from individuals with these CNVs involving deletion versus duplication likewise often differential phenotypes (increases or decreases) in the categories shown. Figure created with BioRender.com.
拷贝数变异（CNVs）涉及人类基因组易感区间的重复或缺失，是多种神经发育和神经精神疾病的基础。由于这些疾病的可及性体内动物模型通常无法生成，因此可以从携带这些 CNV 的患者中衍生出诱导多能干细胞（iPSC）模型，揭示导致这些疾病的脑发育和神经元功能改变。涉及特定基因组区间缺失与重复的 CNV 通常导致截然不同的临床表型和不同的表型外显率。这篇综述最初侧重于 15q13.3 上的 CNVs，这些 CNVs 与自闭症谱系障碍、注意力缺陷/多动障碍和精神分裂症有关。与大多数 CNVs 一样，15q13.3 的缺失通常导致严重的临床表型，而重复则导致高度可变的外显率，一些携带者没有表现出临床表型。在这里，我们描述了源自 15q13.3 重复和缺失的 iPSC 衍生神经元模型中观察到的细胞和分子表型，这些表型可能有助于解释不同的临床后果和表型外显率。然后，我们将这项工作与涉及重复和缺失的许多其他 CNVs 联系起来，总结 iPSC 研究的发现及其与临床表型的关系。总的来说，这项工作强调了涉及重复与缺失的 CNVs 如何差异地改变神经发育和功能，从而导致神经精神疾病。这些疾病的 iPSC 衍生神经元模型可用于了解潜在的神经发育改变，以及开发表型挽救的药理学或分子方法，这可能为患者干预提供线索。上图：同一基因组区间的缺失与重复导致不同的临床表型和不同程度的表型外显率。示意性地总结了示例发现。下图：来自携带这些涉及缺失与重复的 CNV 的个体的 iPSC 衍生神经元通常在所示类别中表现出不同的表型（增加或减少）。该图使用 BioRender.com 创建。
