Notably, these differentially expressed genes included previously identified ASD-associated genes and are enriched for genes in ASD-associated weighted gene co-expression networks. RNA sequencing revealed 339 genes differentially expressed between patient- and control-derived organoids of which a subset are implicated in cell proliferation and neurogenesis. The observed phenotypes were rescued after correction of the pathogenic mutation using CRISPR-Cas9. Patient-derived organoids displayed an increase in total volume that was driven by an increased proliferation in neural progenitor cells, leading to an increase in the generation of cortical neuronal and non-neuronal cell types. Patients carrying the c.3709DelG mutation in CNTNAP2 present with an increased head circumference and brain MRI reveals an increase in gray matter volume. In this study, we utilized forebrain organoids generated from hiPSCs derived from patients from the Old Order Amish community with a rare syndromic form of ASD, carrying a homozygous c.3709DelG mutation in CNTNAP2 and healthy controls to investigate the effects of this mutation on cortical embryonic development. The recent development of forebrain organoids generated from human induced pluripotent stem cells (hiPSCs) derived from subjects with brain disorders is a promising method to study human-specific neurobiology, and may facilitate the development of novel therapeutics. Written in the highly successful Methods in Molecular Biology™ series format, chapters contain introductions to their respective topics, lists of the necessary materials and reagents, step-by-step, readily reproducible laboratory protocols, and notes on troubleshooting and avoiding known pitfalls.Īuthoritative and accessible, Genomic Structural Variants: Methods and Protocols provides complete comprehensive coverage of this burgeoning field.Autism spectrum disorder (ASD) represents a major public health burden but translating promising treatment findings from preclinical non-human models of ASD to the clinic has remained challenging. Specific patient groups where copy number variation has been shown to be of great importance are highlighted, and implications for both pre-natal and standard diagnostics are described. It covers the major technologies used for research and diagnostics as well as web-based resources for variation data, and it then goes into depth regarding specific regions of the genome that differ in variation content. Genomic Structural Variants: Methods and Protocols provides an in-depth description of the developments in our understanding of structural genetic variation and its implications for human disease, from the introduction of microarrays up to current state-of-the-art sequencing strategies. Characterization of copy number variation and other forms of structural genetic variation has highlighted the complexity of human genetic variation and also provided significant insight into the evolution and dynamic nature of our genome. The development of array-based strategies made it possible to look at our genome in new ways and for new types of variation to be discovered and characterized. The completion of a consensus draft sequence for the human genome was the starting point for more thorough investigations of individual genome variation.
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