Deciphering mechanisms of altered neurodevelopment in BAF complex intellectual disability disorders (360G-Wellcome-209568_Z_17_Z)

Intellectual developmental disorder (IDD) is a common yet poorly understood condition. Recent advances in genomic diagnostic technologies have revealed that disruption of genes involved in transcriptional regulation is a leading cause of IDD. Genes encoding the chromatin remodelling BAF swi/snf complex are among the most commonly mutated. Filling the knowledge gap between mutation and disease will contribute to improved patient care and to our overall understanding of human brain development. To that end, I will bridge the clinical and neurodevelopmental biology fields using patient-phenotype informed cellular models to investigate the molecular underpinnings of disease. I will perform deep-phenotyping of a cohort of patients with BAF-complex mutations, and correlate clinical and psychometric features with gene expression and epigenetic signatures in primary tissues. Alongside this clinical study, I will investigate the specific role of ARID1A, an essential BAF complex subunit, in neurodevelopment. Those investigations, performed in induced pluripotent stem cell (iPSC) models of human neurodevelopment, will inform subsequent studies in iPSCs generated from patients. Detailed understanding of clinical outcomes will improve patient management, and integrating the cellular and molecular defects in in vitro models with clinical and molecular phenotypes in patients will help establish predictive preclinical models for translational research.