Establishment of high throughput variants of unknown significance assessment technique - neurodevelopmental gene GABBR2 as a target (KAP200013). unidentified

We propose that brain development, requiring complex orchestrations of many genes and cells, can provide a perfect platform to study variant function and its phenotypic outcome. More specifically, fine tuning of GABA signaling is critical in synapse formation and neural signal transmission. We recently reported a group of pathogenic variants in GABA B receptor 2 (GABBR2) and demonstrated its critical role as a determinant of neurodevelopmental symptoms. However, how a subtle perturbation of GABA B signaling gives rise to differential developmental problems remains unclear. Therefore, we will utilize GABBR2 as a tool to quantify unknown variant function and their phenotypic output. We hypothesize that precise modulation of GABA B signaling determines neurodevelopmental phenotype, and plan to conduct three specific aims as follows. First, monitor human genotype-phenotype correlation of GABBR2. Second, document genotype-function correlation in a high-throughput and quantitative manner. Finally, analyze mouse genotype- phenotype correlation using single cell transcriptome profiling and nascent transcript labeling techniques. Successful completion of these aims will lead to the novel paradigm of variant function interpretation and deeper understanding of neurodevelopmental disorders.