Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, 11042 Belgrade, 152, Serbia.
Department of Medical Genetics, Oslo University Hospital, 0424, Oslo, Norway.
Mol Autism. 2020 Jun 1;11(1):42. doi: 10.1186/s13229-020-00343-4.
Patients diagnosed with chromosome microdeletions or duplications, known as copy number variants (CNVs), present a unique opportunity to investigate the relationship between patient genotype and cell phenotype. CNVs have high genetic penetrance and give a good correlation between gene locus and patient clinical phenotype. This is especially effective for the study of patients with neurodevelopmental disorders (NDD), including those falling within the autism spectrum disorders (ASD). A key question is whether this correlation between genetics and clinical presentation at the level of the patient can be translated to the cell phenotypes arising from the neurodevelopment of patient induced pluripotent stem cells (iPSCs).Here, we examine how iPSCs derived from ASD patients with an associated CNV inform our understanding of the genetic and biological mechanisms underlying the aetiology of ASD. We consider selection of genetically characterised patient iPSCs; use of appropriate control lines; aspects of human neurocellular biology that can capture in vitro the patient clinical phenotype; and current limitations of patient iPSC-based studies. Finally, we consider how future research may be enhanced to maximise the utility of CNV patients for research of pathological mechanisms or therapeutic targets.
被诊断为染色体微缺失或重复的患者，即拷贝数变异（CNVs），为研究患者基因型与细胞表型之间的关系提供了一个独特的机会。CNVs 具有较高的遗传穿透性，并在基因座与患者临床表型之间提供了很好的相关性。这对于研究神经发育障碍（NDD）患者，包括自闭症谱系障碍（ASD）患者，特别有效。一个关键问题是，这种患者水平的遗传与临床表现之间的相关性是否可以转化为患者诱导多能干细胞（iPSC）神经发育产生的细胞表型。在这里，我们研究了源自患有相关 CNV 的 ASD 患者的 iPSC 如何帮助我们了解 ASD 病因的遗传和生物学机制。我们考虑了选择具有遗传特征的患者 iPSC；使用适当的对照系；可以在体外捕获患者临床表型的人类神经细胞生物学方面；以及基于患者 iPSC 的研究目前的局限性。最后，我们考虑如何加强未来的研究，以最大限度地提高 CNV 患者在研究病理机制或治疗靶点方面的效用。
