Next-generation sequencing technologies have revolutionized the ability to identify genetic changes associated with disease. Historically, it was expected that most disease-causing mutations would affect the parts of the genome encoding proteins, but accumulating evidence indicates the importance of mutations in non-protein coding genome regions. Compared to proteins, the disease significance of non-coding regions is still poorly understood. This goal of this proposal is to better understand the non-protein coding genomic regulators of skin disease by focusing on subjects with uncommon mosaic forms of disease using a multimodal approach that combines chromatin profiling and whole genome sequencing. Genetic variations will be functionally characterized by regenerating candidate mutant disease genotypes in human organoids, as well as by rescuing disease organoid tissues by genetic correction of the underlying noncoding mutation. At the end of this proposal, we aim to better understand non-coding genomic regulators of tissue development by innovating a combined strategy of rare mosaic disease research and multi-omics approaches.