Exome sequencing and optical genome mapping in molecularly unsolved cases of duchenne muscular dystrophy

  • Duchenne muscular dystrophy (DMD) is a severe progressive muscle disease that mainly affects boys due to \(\it X\)-linked recessive inheritance. In most affected individuals, MLPA or sequencing-based techniques detect deletions, duplications, or point mutations in the dystrophin-encoding \(\it DMD\) gene. However, in a small subset of patients clinically diagnosed with DMD, the molecular cause is not identified with these routine methods. Evaluation of the 60 DMD patients in our center revealed three cases without a known genetic cause. DNA samples of these patients were analyzed using whole-exome sequencing (WES) and, if unconclusive, optical genome mapping (OGM). WES led to a diagnosis in two cases: one patient was found to carry a splice mutation in the \(\it DMD\) gene that had not been identified during previous Sanger sequencing. In the second patient, we detected two variants in the fukutin gene \(\it (FKTN)\) that were presumed to be disease-causing. In the third patient, WES was unremarkable, but OGM identified an inversion disrupting the \(\it DMD\) gene (~1.28 Mb) that was subsequently confirmed with long-read sequencing. These results highlight the importance of reanalyzing unsolved cases using WES and demonstrate that OGM is a useful method for identifying large structural variants in cases with unremarkable exome sequencing.

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Author:Leoni S. ErbeGND, Sabine HoffjanGND, Sören JanßenGND, Moritz KneifelGND, Karsten KrauseGND, Wanda Maria GerdingORCiDGND, Kristina DöringORCiDGND, Anne-Katrin GüttschesORCiDGND, Andreas RoosORCiDGND, Elena Buena AtienzaGND, Caspar GrossORCiDGND, Thomas LückeGND, Huu Phuc NguyenORCiDGND, Matthias VorgerdORCiDGND, Cornelia KöhlerGND
Parent Title (English):International journal of molecular sciences
Subtitle (English):identification of a causative \(\it X\)-chromosomal inversion disrupting the \(\it DMD\) gene
Place of publication:Basel
Document Type:Article
Date of Publication (online):2024/03/19
Date of first Publication:2023/09/28
Publishing Institution:Ruhr-Universität Bochum, Universitätsbibliothek
Tag:Open Access Fonds
DMD; Duchenne muscular dystrophy; FKTN; OGM; dystrophin; fukutin; inversion; long-read sequencing; optical genome mapping; whole-exome sequencing
Issue:19, Article 14716
First Page:14716-1
Last Page:14716-16
Article Processing Charge funded by the Deutsche Forschungsgemeinschaft (DFG) and the Open Access Publication Fund of Ruhr-Universität Bochum.
Institutes/Facilities:Medizinische Fakultät, Abteilung für Humangenetik
Centrum für Seltene Erkrankungen Ruhr (CeSER)
Dewey Decimal Classification:Technik, Medizin, angewandte Wissenschaften / Medizin, Gesundheit
open_access (DINI-Set):open_access
faculties:Medizinische Fakultät
Licence (English):License LogoCreative Commons - CC BY 4.0 - Attribution 4.0 International