To what extent are de novo DNA rearrangements in the human genome responsible for sporadic human disease traits? How many human Mendelian and complex traits, as well as sporadic genomic disorders, developmental disabilities and birth defects, are due to structural changes and/or gene copy number variants (CNV)? To what extent is secondary structure mutagenesis, rather than W-C base pair changes, underlying variant alleles and human disease traits? What are the molecular mechanisms for human genomic rearrangements and structural variant (SV) mutagenesis? The answers to these questions will impact both prenatal and postnatal molecular diagnostics, as well as patient and family management and therapeutics. Moreover, the answers have profound implications for organismal developmental biology, biological homeostasis, and human gene and human genome evolution.