Gene Discovery and Glutamate Signaling Defects in Intellectual Disability and Autism
Niranjan, Tejasvi S.
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Neurodevelopmental disorders are a common class of brain disorders that affect up to 1 in 6 children in the industrialized world. They include a range of diseases, including Attention Deficit Hyperactivity Disorder, Autism Spectrum Disorders, and various forms Intellectual Disability. Many of these disorders display overlapping clinical phenotypes, including reductions in intellectual quotient, learning delays, difficulties in social behavior, stereotypical behaviors, and deficits in verbalization and communication. Frequently, other comorbidities may be present, such as epilepsy or craniofacial defects. Many of these disorders are strictly genetic in their etiology, as determined by a consistent pattern of Mendelian inheritance in affected families. Other, more complex neurodevelopmental disorders, such as schizophrenia, major depression, bipolar disorder, and autism, show strong evidence that genetics is a substantial cause, along with a role for environmental factors. The focus of this dissertation will be on elucidating genetic and molecular mechanisms involved in the etiology of two neurodevelopmental disorders, X-Linked Intellectual Disability and Autism Spectrum Disorders. Throughout this dissertation, a series of important observations and concepts will be discussed regarding the challenges faced when studying neurodevelopmental disorders of genetic etiology. These challenges are based in the intersecting complexities of how genetic variation influences neural mechanisms and how neural mechanisms influence intellectual function and behavior. In order to address these challenges, I have developed computational tools to improve our ability to identify potential disease-causing variants and genes. One of these tools is an effective method to identify causal genes in XLID, through improvements in the quality of sequenced variant calls, and through effective methods of variant filtering using a combination of datasets. Lastly, I have employed a series of targeted genomic and functional studies to determine how genetic variation can modify neural function and behavior. This series of studies will discuss the role of glutamate signaling defects in autism etiology, with a focus on Glutamate Receptor Interacting Proteins (GRIP1/2) as autism susceptibility genes. As a whole, these studies should provide a framework demonstrating how old and new genomic techniques can be used effectively to find disease-causing variants and genes in neurodevelopmental disorders of increasing complexity. Importantly, this work should reinforce our appreciation of the complexity of neural and genetic systems, and that any computational inference should be diligently investigated by functional work to identify a molecular mechanism for disease.