Abstract
BACKGROUND: Duchenne muscular dystrophy (DMD) is a severe disorder that primarily affects males due to its X-linked recessive inheritance. It is caused by pathogenic variants of the DMD gene, most commonly exonic deletions, duplications, or point mutations. Current routine genetic testing methods, including next-generation sequencing and multiplex ligation-dependent probe amplification, can identify pathogenic DMD variants in over 90% of clinically diagnosed patients. However, in rare cases, a molecular diagnosis cannot be established using routine methods. CASE PRESENTATION: We describe a follow-up genetic analysis, based on karyotyping and optical genome mapping (OGM), of a patient with clinically diagnosed DMD who initially had negative results in extensive routine genetic testing. Karyotyping revealed a paracentric X-chromosomal inversion with estimated breakpoints at p22.31 and p21.2. OGM fine-mapped this alteration as inv(X)(p22.2p21.1) and confirmed its pathogenicity by identifying the proximal breakpoint within intron 41 of DMD, thereby disrupting the gene and providing a definitive molecular genetic diagnosis. CONCLUSIONS: Current results further underscore the important role of chromosomal inversions as causal in a subset of DMD patients who remain without a molecular diagnosis after routine testing. It also demonstrates the utility of OGM in providing detailed, gene-level insights into cytogenetic abnormalities observed in the diagnostics of neuromuscular disorders.