ABSTRACT Suboptimal myelination of the brain, whether developmental or degenerative, has major ramifications on function. Abnormal myelin slows nerve conduction and signal synchronicity with consequences such as seizures, intellectual disability, autism and accelerated age-related cognitive decline. We have identified an approximately 1.6 megabase region of human chromosome 18q23 that when hemizygous results in a failure of myelin to develop normally. However, it is not yet known if the cause of this dysmyelination is due to haploinsufficiency of one of the gene products or a synergistic effect of more than one gene in the critical genomic region. In this proposal, we have created a team of both clinical and basic scientists to address this question. Together, we will acquire sufficient data to formulate a successful experimental system to define the cellular consequences of the causal genetic defect(s) at 18q23 on oligodendrocyte proliferation, maturation and myelin function both in mice and in human in vitro models. We will develop an integrated pipeline to perform rescue experimentation in human and mouse models that will lead to development of high throughput assays for drug screening experiments in which to test successful compounds on correcting or improving the dysmyelination defect at key stages of development. For this project, we will generate induced pluripotent stem cells (iPSC) from 3 individuals who are mosaic for a chromosome 18q23 deletion thereby creating sets of isogenic positive and negative control lines. From these we will derive myelinating cortical spheroid models to comprehensively evaluate for myelination abnormalities as compared to their controls with genomic background that differs only at the 18q23 locus. At the same time we will use siRNA silencing of the conserved 18q23 genes in mouse brain cells to define roles in myelinogenesis and compare to the myelin characteristics observed in the human 18q23- model. Correlation of the human and mouse data are essential in order to develop a live mouse model that recapitulates the human condition and can then be used for drug toxicity and effectiveness screening in combination with the human in vitro models. In turn, the longitudinal program of the Chromosome 18 Clinical Research Center maintains close contact with the largest cohort of individuals with chromosome 18 abnormalities, thus making it well positioned to inform interpretation of experimental results as well as conduct clinical trials based on findings from these results.