Transcriptome and Genome Analysis Uncovers a DMD Structural Variant: A Case Report

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. We performed genomic SRS, skeletal muscle transcriptome sequencing, and targeted programmable long-read sequencing (LRS). 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. 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.