Abstract
Duchenne muscular dystrophy (DMD) is a rare genetic disorder caused by the absence of a fully functional dystrophin protein in myocytes. In skeletal muscle, the lack of dystrophin ultimately results in muscle wasting and the replacement of myocytes with fatty or fibrous tissues. In the heart, cardiomyocytes eventually fail and cause fatal cardiomyopathy. We present a case of a male patient and his younger brother with a maternally inherited inverted insertion of approximately 306 kb of chromosome 10 in the deep intronic region between exons 44 and 45 of the DMD gene, leading to Duchenne muscular dystrophy. Chromosomal microarray, comprehensive muscular dystrophy genetic testing, and whole exome sequencing were negative. Targeted transcriptome RNA sequencing at an external lab showed no aberrant splicing. Research whole genome sequencing identified the copy number gain and insertion. Subsequent reanalysis of the RNA sequencing data showed possible aberrant splicing involving DMD exons 44-45, and research RNA sequencing revealed a fusion between the DMD gene on the minus strand of chromosome X and the PFKFB3 gene on the plus strand of chromosome 10. We demonstrate that whole genome sequencing can be valuable for identifying intronic events in the DMD gene previously undetected or not reported by traditional clinical testing.