A novel deep intronic variant introduce dystrophin pseudoexon in Becker muscular dystrophy: A case report

Most pathogenic DMD variants are detectable and interpretable by standard genetic testing for dystrophinopthies. However, approximately 1∼3% of dystrophinopthies patients still do not have a detectable DMD variant after standard genetic testing, most likely due to structural chromosome rearrangements and/or deep intronic pseudoexon-activating variants. Here, we report on a boy with a suspected diagnosis of Becker muscular dystrophy (BMD) who remained without a detectable DMD variant after exonic DNA-based standard genetic testing. Dystrophin mRNA studies and genomic Sanger sequencing were performed in the boy, followed by in silico splicing analyses. We successfully detected a novel deep intronic disease-causing variant in the DMD gene (c.2380 + 3317A > T), which consequently resulting in a new dystrophin pseudoexon activation through the enhancement of a cryptic donor splice site. The patient was therefore genetically diagnosed with BMD. Our case report further emphasizes the significant role of disease-causing splicing variants within deep intronic regions in genetically undiagnosed dystrophinopathies.