Key result
Optical genome mapping identifies pathogenic DMD structural variations in ~75% of patients with inconclusive conventional testing.
Why the study?
Approximately 7% of individuals with dystrophinopathy remain undiagnosed at the genetic level using conventional genetic tests like MLPA and NGS.
Does optical genome mapping improve the detection of complex variations in the DMD gene in patients with dystrophinopathy undiagnosed by conventional methods?
Observational (n=8)
Does optical genome mapping improve the detection of complex variations in the DMD gene in patients with dystrophinopathy undiagnosed by conventional methods?
Absolute Event Rate: 75% vs 25%
Optical genome mapping is a valuable diagnostic tool for identifying complex structural variations in dystrophinopathy patients who remain undiagnosed after conventional genetic testing.
May support targeted testing in unresolved dystrophinopathy; hypothesis-generating given case-report design.
OBJECTIVE: Approximately 7% of individuals with dystrophinopathy remain undiagnosed at the genetic level using conventional genetic tests like multiplex ligation-dependent probe amplification (MLPA) and next-generation sequencing (NGS). We used the optical genome mapping (OGM) technology to detect and analyze uncommon mutations or structural variations (SVs) within the DMD gene, thus contributing to more precise clinical diagnoses. METHODS: We herein included eight patients with dystrophinopathy (six males and two females) in whom pathogenic variants of the DMD gene could not be accurately identified using MLPA and NGS. Clinical data were collected for all patients and genetic testing was performed using OGM. RESULTS: Conventional methods (MLPA and NGS) failed to detect pathogenic mutations in six out of eight individuals (four males and two females). OGM testing uncovered rare mutations in the DMD gene in four patients, including a pericentric inversion in chromosome X (one male), a complex rearrangement (one male), and two X-autosome translocations (two females). No mutations were detected in the remaining two male patients. OGM also accurately mapped balanced X-autosome translocations in female patients, defining chromosomal breakpoints. In the other two male patients in whom MLPA suggested non-contiguous exon duplications or deletions in the DMD gene, OGM characterized one case as a complex rearrangement and the other as a deletion within the DMD gene. INTERPRETATION: OGM is a valuable diagnostic tool for dystrophinopathy patients with negative results from conventional genetic tests. It can effectively elucidate complex SVs and pinpoint breakpoints in X-autosomal translocations in female patients, facilitating prompt and appropriate interventions.
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Mai et al. (2024) conducted an observational in Dystrophinopathy (n=8). Optical genome mapping (OGM) vs. Conventional genetic tests (MLPA and NGS) was evaluated on Detection and characterization of pathogenic mutations or structural variations in the DMD gene. Optical genome mapping identified or characterized pathogenic structural variations in the DMD gene in 75% (6 of 8) of dystrophinopathy patients with inconclusive conventional genetic testing.
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