Donders Institute for Brain, Cognition and Behaviour
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Thesis defense Shan Wang (Donders Series 605)

16 May 2023

Promotors: Prof. Hans van Bokhoven; Prof. Nael Nadif Kasri;
Co-promotor: Dr. Dirk Schubert

Modeling the pathogenesis of neurodevelopmental disorders using human induced pluripotent stem cells: From genetics to cellular phenotypes

Neurodevelopmental disorders (NDDs) are a group of heterogeneous disorders with affected brain development, showing deficits in emotion, communication, learning ability and memory. Accumulating evidence supports the heterogeneous etiology of NDDs, involving both genetic factors and environmental cues. The genetic heterogeneity in NDDs is one of the major obstacles in both diagnosis and treatment. Due to the rapid development of next generation sequencing, there has been enormous progress in the identification of NDD-associated genes. Currently, causative monogenic variants in more than 1500 genes have been identified in individuals with a neurodevelopmental phenotype. The challenge in this field is to understand the underlying pathophysiology of NDDs, including the determination of the involved brain regions and cell types, the normal and disrupted properties of the affected genes and proteins, and the developmental window of the pathological effects exerted by these genes. This thesis aims to get a better understanding of these processes for two genes that have been implicated in NDDs, SETD1A and EHMT1.  Studies in this thesis uncovered new mechanistic insights into the role of SETD1A in neuronal development, and the astroglial role of EHMT1 in neuronal network dysfunction. These findings offer promising therapeutic targets for further investigation and could potentially benefit patients with SETD1A variants or EHMT1 variants.