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OBJECTIVE: Duchenne muscular dystrophy (DMD) is caused by pathogenic variants in the dystrophin gene (). Hypermethylated CGG expansions within 5' UTR are associated with an intellectual development disorder. Here, we demonstrate the diagnostic utility of genomic short-read sequencing (SRS) and transcriptome sequencing to identify a novel structural variant (SV) and a CGG expansion in a patient with DMD for whom conventional diagnostic testing failed to yield a genetic diagnosis.METHODS: We performed genomic SRS, skeletal muscle transcriptome sequencing, and targeted programmable long-read sequencing (LRS).RESULTS: The proband had a typical DMD clinical presentation, autism spectrum disorder (ASD), and dystrophinopathy on muscle biopsy. Transcriptome analysis identified 6 aberrantly expressed genes; and were the strongest underexpression and overexpression outliers, respectively. Genomic SRS identified a 216 kb paracentric inversion (NC_000023.11: g.33162217-33378800) overlapping 2 promoters. ExpansionHunter indicated an expansion of 109 CGG repeats within the 5' UTR of . Targeted genomic LRS confirmed the SV and genotyped the repeat expansion as 270 CGG repeats.DISCUSSION: Here, transcriptome data heavily guided genomic analysis to resolve a complex inversion and a repeat expansion. Longitudinal follow-up will be important for clarifying the clinical significance of the genotype.