Expanding the Molecular Genetic Landscape of Dystrophinopathies and Associated Phenotypes
Katja Neuhoff,
Ozge Aksel Kilicarslan,
Corinna Preuße,
Ann-Kathrin Zaum,
Heike Kölbel,
Hanns Lochmüller,
Ulrike Schara-Schmidt,
Kiran Polavarapu,
Andreas Roos,
Andrea Gangfuß
Affiliations
Katja Neuhoff
Department of Pediatric Neurology, Centre for Neuromuscular Disorders, Centre for Translational Neuro- and Behavioral Sciences, University Duisburg-Essen, 45122 Essen, Germany
Ozge Aksel Kilicarslan
Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 5B2, Canada
Corinna Preuße
Department of Neuropathology, Charité-University Medicine Berlin, 10117 Berlin, Germany
Ann-Kathrin Zaum
Institute of Human Genetics, University of Würzburg, 97074 Würzburg, Germany
Heike Kölbel
Department of Pediatric Neurology, Centre for Neuromuscular Disorders, Centre for Translational Neuro- and Behavioral Sciences, University Duisburg-Essen, 45122 Essen, Germany
Hanns Lochmüller
Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 5B2, Canada
Ulrike Schara-Schmidt
Department of Pediatric Neurology, Centre for Neuromuscular Disorders, Centre for Translational Neuro- and Behavioral Sciences, University Duisburg-Essen, 45122 Essen, Germany
Kiran Polavarapu
Children’s Hospital of Eastern Ontario Research Institute, Ottawa, ON K1H 5B2, Canada
Andreas Roos
Department of Pediatric Neurology, Centre for Neuromuscular Disorders, Centre for Translational Neuro- and Behavioral Sciences, University Duisburg-Essen, 45122 Essen, Germany
Andrea Gangfuß
Department of Pediatric Neurology, Centre for Neuromuscular Disorders, Centre for Translational Neuro- and Behavioral Sciences, University Duisburg-Essen, 45122 Essen, Germany
Background/Objectives: X-linked dystrophinopathies are a group of neuromuscular diseases caused by pathogenic variants in the DMD gene (MIM *300377). Duchenne muscular dystrophy (DMD; MIM #310200) is the most common inherited muscular dystrophy. Methods: We screened datasets of 403 male, genetically confirmed X-linked dystrophinopathy patients and identified 13 pathogenic variants of the DMD gene that have not been described in the literature thus far. For all patients we provide additional data on the clinical course, genotype–phenotype correlations as well as histological datasets of nine patients. In two cases, we used RNA-Seq analyses, showing that this method can be particularly helpful in cases of deep intrinsic variants. Results: We were able to show, that a combination of the different datasets is helpful to counsel families and provides a better understanding of the underlying pathophysiology. Conclusions: Overall, we elaborated upon the persistent challenge of determining the course of disease from genetic analysis alone, rather supporting the concept of a clinical continuum of dystrophinopathies with our combined clinical, histological and molecular genetic findings.
