Moritz Kneifel (Bochum / DE), Sören Janßen (Bochum / DE), Dr Cornelia Köhler (Bochum / DE), Prof. Thomas Lücke (Bochum / DE), Stephan Ossowski (Tübingen / DE), Priv. Doz. Dr. Sabine Hoffjan (Bochum / DE), Prof. Huh Phuc Ngyuen (Bochum / DE), Leoni Erbe (Bochum / DE), Wanda Maria Gerding (Bochum / DE), PD Dr.rer nat Andreas Roos (Bochum / DE; Essen / DE), Prof. Dr. Matthias Vorgerd (Bochum / DE)
Abstract-Text (inkl. Referenzen)
Introduction:
Duchenne muscular dystrophy (DMD) is caused by lack of expression of functional full-length dystrophin protein. In most of patients, large deletions or duplications in the DMD gene are causative. Only 7 cases with inversions affecting the DMD gene are described. Muscle pathology is characterized in two of these cases.
Methods:
To elucidate the molecular genetic cause of a muscular dystrophy in a male patient presenting with elevated CK (up to 17,000 U/l), optical genome mapping (OGM) was carried out. Microscopic studies were performed to characterize muscle pathology.
Results:
OGM revealed a hemizygous inversion of approximately 1.28 Mb partially affecting the DMD gene. As the variant could not be detected by MLPA or NGS, way to genetic diagnosis lasted two decades. Re-analysis of the archived muscle biopsy (collected at one year of age) showed endomysial fibrosis, fiber size variations, internal nuclei, hypercontractile fibers and inflammatory infiltrates. Immunofluorescence studies revealed a partial DMD expression (DYS1) accompanied by decrease of SGCD and DRP2 as well as absence of DYS2, DYS3, SGCB, SGCA and SGCG. LAMA5 and MHCn were increased.
Discussion:
Our results extend the molecular genetic landscape of DMD and highlight that OGM hold the potential to unravel pathogenic DMD variants not detectable by common approaches. Moreover, we present the most comprehensive description of muscle pathology in a "DMD-inversion case" described thus far.