PROJECT SUMMARY/ABSTRACT Individualized diagnosis and treatment based on the integration of clinical, genomic, epigenetic and other biomarkers represent the promise of precision medicine. While most precision medicine initiatives are geared towards cancer treatment and common disease, which affect more than 5% of the population, this proposal seeks to bring the goals of precision medicine to those affected by rare Mendelian genetic diseases. The goal of my research group is to unravel the relationships between Mendelian and common disease through the lens of rare Mendelian syndromes. Our overarching approach will integrate multiple functional genomic studies (RNA-seq and ChIP-seq) from patients with rare Mendelian syndromes to publically available genome wide association study (GWAS) data. Using these data, we will achieve the parallel objectives of 1) revealing the underlying biological mechanisms of rare disease and 2) their intersection with genetic loci associated with common diseases. We will focus our study on the novel genetic syndrome of global developmental delay that we first identified as caused by de novo mutations in KAT6A (Lysine (K) acetyltransferase 6A). KAT6A belongs to a family of acetyltransferase genes and one of its main functions is to modify histones and control the expression of a wide set of downstream genes. In Aim 1, we will identify KAT6A target genes using patient- derived dermal fibroblast cell lines and generate functional genomic data such as RNA-seq and ChIP-seq. These data will be integrated to identify high priority target genes and functionally validated in human cell lines. Aim 2 will address the hypothesis that Mendelian disease mutations affect expression of genes underlying common disease (i.e. autoimmune disease, autism) thereby altering the risk of common disease. Neurocognitive, behavioral and developmental phenotyping will be performed to quantify co-existing common disease phenotypes and will be integrated with individual functional genomic data and disease-specific GWAS. Findings from these studies will advance our ability to interpret the influence of Mendelian gene mutations on common disease loci within a single individual, thus providing a critical link between Mendelian and common disease. In doing so, we will advance precision medicine approaches with respect to Mendelian disease, with the ultimate goal of identifying rational gene targets to use in identification of future therapies for these rare conditions.