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Genomic inversions are a class of DNA structural variation (SV) that usually present with two breakpoints and subsequent 180-degree longitudinal turn of DNA. Though challenging to detect and resolve using current genomic assays, inversions are relevant in evolution, speciation, and human disease pathogenesis through positional effects, gene interruption and altering gene expression.

To fully resolve the genomic structure in a cohort of individuals with MECP2 duplication syndrome (MIM#: 300260) as well as a complex presentation of Coffin-Siris Syndrome (MIM#: 135900) we employed a combination of genomic and molecular methods including classical karyotyping, array comparative genomic hybridization, droplet digital PCR, short-read whole-genome sequencing, and genomic optical mapping. The visualization of long lengths of unbroken DNA molecules through methods like genomic optical mapping is critical in properly studying a mutational event resulting in a genomic structural variant. As the role of SVs in gene disruption and dosage expression of pathogenic alleles causing human disease traits becomes more clear, new methods like optical mapping may be required to study individual structural aberrations in their totality.