Reclassification of intragenic DMD gene duplications by optical genome mapping resolves uncertainty and improves...

Pathogenic copy number and sequence variants in the dystrophin (DMD) gene cause X-linked dystrophinopathies. Predicting the clinical consequences of intragenic DMD duplications is challenging because their functional impact depends on the physical location of the duplicated material, which cannot be determined through conventional testing. Optical genome mapping is a method of structural variant analysis that can identify both the quantity and location of rearranged segments. We report three male patients with intragenic DMD duplications whose significance was revised using clinical optical genome mapping. Two were inserted outside of the DMD gene and reclassified as likely benign. The third was situated in tandem with the original sequence and reclassified as pathogenic. These cases emphasize the importance of evaluating the genomic location of DMD duplications, particularly when the patient's phenotype does not align with their genotype classification, and highlight the implications for clinical management and genetic counseling.