Somatic mosaicism due to a reversion variant causing hemi-atrophy: a novel variant of dystrophinopathy

Abstract

We describe a case of hemi-atrophy in a young adult male, with a positive family history of three maternal uncles with Duchenne muscular dystrophy (DMD). The patient showed progressive weakness localized to the left side, an abnormal electromyography, and creatine kinase levels 43000 IU/l. Muscle biopsy showed both dystrophin-positive and -negative myofibers. An out-of-frame duplication variant in DMD, that is, c.(93+1_94-1)_(649+1_650-1)dup(p.?) resulting in duplication of exons 3-7 was inherited, but the muscle biopsy showed dystrophin mRNA with and without the duplication. Dystrophin quantification using mass spectrometry showed 25% normal dystrophin protein levels in the muscle biopsy from the stronger right side. Sex chromosome aneuploidy was ruled out. We conclude that the patient inherited the duplication variant, but early in development an inner cell mass underwent a somatic recombination event removing the duplication and restoring dystrophin expression. To our knowledge, this is the first report of a reversion leading to somatic mosaicism in DMD.

Isolated cardiomyopathy in a pathogenic X‐linked in frame hemizygous DMD exon 49 deletion: A rare presentation with normal creatine kinase levels and absence of musculoskeletal symptoms

“…During the process of differential diagnosis, we considered mosaicism, however samples from leukocytes and cheek epithelium validated the exon 49 deletion. A previous case report in the literature described a patient with isolated cardiomyopathy and somatic mosaicism in DMD; however, this patient exhibited hemi-atrophy and external findings suggestive of mosaicism, which were not present in the current case (Punetha et al, 2016). We also considered X chromosome aneuploidy such as 47, XXY but both tests reported hemizygosity.…”