Optical Genome Mapping and Long-Read Sequencing Identifies a Novel Dystrophin Gene Inversion in a Patient With...

Genetic testing using targeted panels or comprehensive genome sequencing is the current standard for diagnosing Duchenne muscular dystrophy (DMD), identifying pathogenic variants in up to 98% of cases. We report a 5-year-old male presenting with delayed motor milestones, frequent falls, and difficulty climbing stairs due to generalized muscle weakness. Laboratory studies revealed markedly elevated CK (13,041 U/L) and chronic transaminase elevation. Clinical examination demonstrated Gower's sign, calf pseudohypertrophy, neuromuscular scoliosis, and cognitive impairment. Initial neuromuscular gene panel testing identified several variants of uncertain significance, and muscle biopsy showed markedly reduced dystrophin labeling. Follow-up short-read DMD sequencing with deletion/duplication analysis at Age 11 remained negative. Given persistently negative findings, we utilized optical genome mapping (Bionano Genomics) and long-read sequencing (Oxford Nanopore Technologies) to identify potential structural variants. Both methods independently detected a novel inversion identified to span 31 kb and encompassing exons 68-73 of the DMD gene (ChrX: 31,171,362-31,202,982), classified as pathogenic. This case highlights a clinically definitive diagnosis of DMD missed by standard genetic testing. Our findings demonstrate that Optical Genome Mapping and Long-Read Sequencing provide complementary, high-resolution tools for identifying previously unidentified structural variants and should be considered in unresolved cases prior to invasive procedures such as muscle biopsy.