Exome Sequencing and Optical Genome Mapping in Molecularly Unsolved Cases of Duchenne Muscular Dystrophy: Identification of a Causative X-Chromosomal Inversion Disrupting the <i>DMD</i> Gene
Duchenne muscular dystrophy (DMD) is a severe progressive muscle disease that mainly affects boys due to X-linked recessive inheritance. In most affected individuals, MLPA or sequencing-based techniques detect deletions, duplications, or point mutations in the dystrophin-encoding <i>DMD</i&...
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MDPI AG
2023-09-01
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| author | Leoni S. Erbe Sabine Hoffjan Sören Janßen Moritz Kneifel Karsten Krause Wanda M. Gerding Kristina Döring Anne-Katrin Güttsches Andreas Roos Elena Buena Atienza Caspar Gross Thomas Lücke Hoa Huu Phuc Nguyen Matthias Vorgerd Cornelia Köhler |
| author_facet | Leoni S. Erbe Sabine Hoffjan Sören Janßen Moritz Kneifel Karsten Krause Wanda M. Gerding Kristina Döring Anne-Katrin Güttsches Andreas Roos Elena Buena Atienza Caspar Gross Thomas Lücke Hoa Huu Phuc Nguyen Matthias Vorgerd Cornelia Köhler |
| author_sort | Leoni S. Erbe |
| collection | DOAJ |
| description | Duchenne muscular dystrophy (DMD) is a severe progressive muscle disease that mainly affects boys due to X-linked recessive inheritance. In most affected individuals, MLPA or sequencing-based techniques detect deletions, duplications, or point mutations in the dystrophin-encoding <i>DMD</i> 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 <i>DMD</i> gene that had not been identified during previous Sanger sequencing. In the second patient, we detected two variants in the fukutin gene (<i>FKTN</i>) that were presumed to be disease-causing. In the third patient, WES was unremarkable, but OGM identified an inversion disrupting the <i>DMD</i> 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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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T21:42:35Z |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-3ec8e1bd14f54769a046f4c0a9412e162023-11-19T14:30:39ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-09-0124191471610.3390/ijms241914716Exome Sequencing and Optical Genome Mapping in Molecularly Unsolved Cases of Duchenne Muscular Dystrophy: Identification of a Causative X-Chromosomal Inversion Disrupting the <i>DMD</i> GeneLeoni S. Erbe0Sabine Hoffjan1Sören Janßen2Moritz Kneifel3Karsten Krause4Wanda M. Gerding5Kristina Döring6Anne-Katrin Güttsches7Andreas Roos8Elena Buena Atienza9Caspar Gross10Thomas Lücke11Hoa Huu Phuc Nguyen12Matthias Vorgerd13Cornelia Köhler14Department of Human Genetics, Ruhr-University Bochum, 44801 Bochum, GermanyDepartment of Human Genetics, Ruhr-University Bochum, 44801 Bochum, GermanyDepartment of Neuropediatrics, University Children’s Hospital, Ruhr-University Bochum, 44801 Bochum, GermanyDepartment of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil, Ruhr-University Bochum, 44801 Bochum, GermanyDepartment of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil, Ruhr-University Bochum, 44801 Bochum, GermanyDepartment of Human Genetics, Ruhr-University Bochum, 44801 Bochum, GermanyDepartment of Human Genetics, Ruhr-University Bochum, 44801 Bochum, GermanyDepartment of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil, Ruhr-University Bochum, 44801 Bochum, GermanyDepartment of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil, Ruhr-University Bochum, 44801 Bochum, GermanyInstitute of Medical Genetics and Applied Genomics, University Tübingen, 72074 Tübingen, GermanyInstitute of Medical Genetics and Applied Genomics, University Tübingen, 72074 Tübingen, GermanyCenter for Rare Diseases Ruhr (CeSER), 44791 Bochum, GermanyDepartment of Human Genetics, Ruhr-University Bochum, 44801 Bochum, GermanyDepartment of Neurology, Heimer Institute for Muscle Research, University Hospital Bergmannsheil, Ruhr-University Bochum, 44801 Bochum, GermanyCenter for Rare Diseases Ruhr (CeSER), 44791 Bochum, GermanyDuchenne muscular dystrophy (DMD) is a severe progressive muscle disease that mainly affects boys due to X-linked recessive inheritance. In most affected individuals, MLPA or sequencing-based techniques detect deletions, duplications, or point mutations in the dystrophin-encoding <i>DMD</i> 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 <i>DMD</i> gene that had not been identified during previous Sanger sequencing. In the second patient, we detected two variants in the fukutin gene (<i>FKTN</i>) that were presumed to be disease-causing. In the third patient, WES was unremarkable, but OGM identified an inversion disrupting the <i>DMD</i> 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.https://www.mdpi.com/1422-0067/24/19/14716Duchenne muscular dystrophyDMDoptical genome mappingOGMlong-read sequencinginversion |
| spellingShingle | Leoni S. Erbe Sabine Hoffjan Sören Janßen Moritz Kneifel Karsten Krause Wanda M. Gerding Kristina Döring Anne-Katrin Güttsches Andreas Roos Elena Buena Atienza Caspar Gross Thomas Lücke Hoa Huu Phuc Nguyen Matthias Vorgerd Cornelia Köhler Exome Sequencing and Optical Genome Mapping in Molecularly Unsolved Cases of Duchenne Muscular Dystrophy: Identification of a Causative X-Chromosomal Inversion Disrupting the <i>DMD</i> Gene International Journal of Molecular Sciences Duchenne muscular dystrophy DMD optical genome mapping OGM long-read sequencing inversion |
| title | Exome Sequencing and Optical Genome Mapping in Molecularly Unsolved Cases of Duchenne Muscular Dystrophy: Identification of a Causative X-Chromosomal Inversion Disrupting the <i>DMD</i> Gene |
| title_full | Exome Sequencing and Optical Genome Mapping in Molecularly Unsolved Cases of Duchenne Muscular Dystrophy: Identification of a Causative X-Chromosomal Inversion Disrupting the <i>DMD</i> Gene |
| title_fullStr | Exome Sequencing and Optical Genome Mapping in Molecularly Unsolved Cases of Duchenne Muscular Dystrophy: Identification of a Causative X-Chromosomal Inversion Disrupting the <i>DMD</i> Gene |
| title_full_unstemmed | Exome Sequencing and Optical Genome Mapping in Molecularly Unsolved Cases of Duchenne Muscular Dystrophy: Identification of a Causative X-Chromosomal Inversion Disrupting the <i>DMD</i> Gene |
| title_short | Exome Sequencing and Optical Genome Mapping in Molecularly Unsolved Cases of Duchenne Muscular Dystrophy: Identification of a Causative X-Chromosomal Inversion Disrupting the <i>DMD</i> Gene |
| title_sort | exome sequencing and optical genome mapping in molecularly unsolved cases of duchenne muscular dystrophy identification of a causative x chromosomal inversion disrupting the i dmd i gene |
| topic | Duchenne muscular dystrophy DMD optical genome mapping OGM long-read sequencing inversion |
| url | https://www.mdpi.com/1422-0067/24/19/14716 |
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