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Genetics underpins all of biology, and is the most rapidly evolving field in biomedical research. The ASXL gene family are critical players in rare developmental disorders and various cancers, bridging seemingly disparate areas of study. This dissertation provides a comprehensive examination of the role of ASXL1 mutations in the intersection of rare genetic disorders and cancer, highlighting the multifaceted impact across developmental biology, genetics, and metabolism.Chapter 1 explores the broad regulatory roles of the ASXL gene family in developmental and oncogenic processes, detailing the molecular architecture, clinical and epigenetic consequences of ASXL mutations, and identifies potential avenues for research and therapeutic development. Chapter 2 investigates how ASXL1 mutations disrupt epigenetic regulation in Bohring-Opitz Syndrome (BOS) patient-derived tissues, impacting gene expression through dysregulation of Wnt signaling pathways. This cross-tissue effect offers potential therapeutic targets. Chapter 3 also utilizes a multi-omics approach to explore the effect of ASXL1 mutations across development in induced pluripotent stem cells , neural progenitor cells , and neural crest cells, identifying defects in neurodevelopment and cell migration. Chapter 4 delves into metabolic dysregulations in BOS, highlighting mitochondrial dysfunction and metabolic inflexibility that could underlie clinical manifestations of the syndrome. Chapter 5 presents a unique familial case with ASXL1 missense mutation, expanding the phenotypic spectrum associated with ASXL1 mutations and suggesting distinct metabolic phenotypes.In Chapter 6, a direct comparison of ASXL1 mutations in acute myeloid leukemia and BOS reveals shared molecular pathways, advocating a unified gene-centric approach to studying these disorders. Chapter 7 discusses the implications of BLM gene mutations in clonal hematopoiesis of indeterminate potential genes, linking germline disorders and cancer predisposition. By integrating multi-omics analyses, patient-derived cellular models, and comprehensive metabolic characterizations, this work establishes crucial connections between rare genetic disorders, metabolic defects, and cancer, underscoring the potential for cross-disease insights to inform targeted therapies. This dissertation contributes to our understanding of specific disorders like BOS and reveals shared molecular dysregulations between rare germline disorders and cancer. These findings pave the way for developing targeted therapeutic interventions that could benefit a broad spectrum of conditions.