ObjectiveDuchenne muscular dystrophy (DMD) is caused by pathogenic variants in the dystrophin gene (DMD). Hypermethylated CGG expansions withinDIP2B5′ 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 novelDMDstructural variant (SV) and aDIP2BCGG expansion in a patient with DMD for whom conventional diagnostic testing failed to yield a genetic diagnosis.MethodsWe performed genomic SRS, skeletal muscle transcriptome sequencing, and targeted programmable long-read sequencing (LRS).ResultsThe proband had a typical DMD clinical presentation, autism spectrum disorder (ASD), and dystrophinopathy on muscle biopsy. Transcriptome analysis identified 6 aberrantly expressed genes;DMDandDIP2Bwere the strongest underexpression and overexpression outliers, respectively. Genomic SRS identified a 216 kb paracentric inversion (NC_000023.11: g.33162217-33378800) overlapping 2DMDpromoters. ExpansionHunter indicated an expansion of 109 CGG repeats within the 5′ UTR ofDIP2B. Targeted genomic LRS confirmed the SV and genotyped theDIP2Brepeat expansion as 270 CGG repeats.DiscussionHere, transcriptome data heavily guided genomic analysis to resolve a complexDMDinversion and aDIP2Brepeat expansion. Longitudinal follow-up will be important for clarifying the clinical significance of theDIP2Bgenotype.
