Approaching mosaicism for the genomic odyssey of rare and undiagnosed diseases

Mosaicism is a fundamental biological phenomenon with broad implications for human health and disease. This thesis firmly establishes that postzygotic genetic variation arising at distinct developmental stages can lead to a diverse array of phenotypes, ranging from subtle pigmentary changes to severe multisystem disorders. The difficulties and limitations in detecting somatic mosaicism hinder definitive diagnosis of the affected individuals, yet the knowledge and data regarding its genetic basis remain limited. With a particular focus on selected syndromes/cases that exhibit segmental and/or cutaneous findings, we aimed to address these challenges by confirming clinical diagnoses of individuals in this patient group at the genomic level using advanced molecular and cytogenetic diagnostic techniques. The study is structured around two key components: a cohort presumptive for PIK3CA-related overgrowth spectrum syndromes and a series of single-case studies involving diverse mosaic phenotypes. Patients with clinical findings suggestive of mosaicism were evaluated using a multimodal diagnostic approach. By integrating thorough clinical phenotyping with genomic analyses, we identified, characterized, and redefined the molecular basis of various rare mosaic disorders. These findings encompass variants in crucial biological pathways, including the PI3K-AKT-mTOR and RAS-RAF-MAPK pathways, along with the components of cell-cycle regulation, mitochondrial dynamics, and chromosomal architecture. This study highlights the significant impact of timing and distribution of postzygotic variants on phenotypic expression and challenges conventional genotype-phenotype paradigms. The findings support the implementation of comprehensive clinical-genomic workflows and suggest that mosaicism can be viewed as a unifying framework for interpreting rare syndromes and complex phenotypes. Ultimately, this work reinforces our understanding of mosaicism as a fundamental, yet poorly understood and poorly explored concept in medical genetics, demonstrating the importance of personalized diagnosis for improved genetic counseling and care for patients and their families. The unresolved cases provide valuable resources for future research and fuel our continued desire to explore the unknown in cell and human biology.