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Exome Sequencing and Optical Genome Mapping in Molecularly Unsolved Cases of Duchenne Muscular Dystrophy: Identification of a Causative X-Chromosomal Inversion Disrupting the DMD 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 DMD gene. However,...
Autores principales: | , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10572545/ https://www.ncbi.nlm.nih.gov/pubmed/37834164 http://dx.doi.org/10.3390/ijms241914716 |
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author | Erbe, Leoni S. Hoffjan, Sabine Janßen, Sören Kneifel, Moritz Krause, Karsten Gerding, Wanda M. Döring, Kristina Güttsches, Anne-Katrin Roos, Andreas Buena Atienza, Elena Gross, Caspar Lücke, Thomas Nguyen, Hoa Huu Phuc Vorgerd, Matthias Köhler, Cornelia |
author_facet | Erbe, Leoni S. Hoffjan, Sabine Janßen, Sören Kneifel, Moritz Krause, Karsten Gerding, Wanda M. Döring, Kristina Güttsches, Anne-Katrin Roos, Andreas Buena Atienza, Elena Gross, Caspar Lücke, Thomas Nguyen, Hoa Huu Phuc Vorgerd, Matthias Köhler, Cornelia |
author_sort | Erbe, Leoni S. |
collection | PubMed |
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 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 DMD gene that had not been identified during previous Sanger sequencing. In the second patient, we detected two variants in the fukutin gene (FKTN) that were presumed to be disease-causing. In the third patient, WES was unremarkable, but OGM identified an inversion disrupting the 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. |
format | Online Article Text |
id | pubmed-10572545 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-105725452023-10-14 Exome Sequencing and Optical Genome Mapping in Molecularly Unsolved Cases of Duchenne Muscular Dystrophy: Identification of a Causative X-Chromosomal Inversion Disrupting the DMD Gene Erbe, Leoni S. Hoffjan, Sabine Janßen, Sören Kneifel, Moritz Krause, Karsten Gerding, Wanda M. Döring, Kristina Güttsches, Anne-Katrin Roos, Andreas Buena Atienza, Elena Gross, Caspar Lücke, Thomas Nguyen, Hoa Huu Phuc Vorgerd, Matthias Köhler, Cornelia Int J Mol Sci Article 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 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 DMD gene that had not been identified during previous Sanger sequencing. In the second patient, we detected two variants in the fukutin gene (FKTN) that were presumed to be disease-causing. In the third patient, WES was unremarkable, but OGM identified an inversion disrupting the 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. MDPI 2023-09-28 /pmc/articles/PMC10572545/ /pubmed/37834164 http://dx.doi.org/10.3390/ijms241914716 Text en © 2023 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Erbe, Leoni S. Hoffjan, Sabine Janßen, Sören Kneifel, Moritz Krause, Karsten Gerding, Wanda M. Döring, Kristina Güttsches, Anne-Katrin Roos, Andreas Buena Atienza, Elena Gross, Caspar Lücke, Thomas Nguyen, Hoa Huu Phuc Vorgerd, Matthias Köhler, Cornelia Exome Sequencing and Optical Genome Mapping in Molecularly Unsolved Cases of Duchenne Muscular Dystrophy: Identification of a Causative X-Chromosomal Inversion Disrupting the DMD Gene |
title | Exome Sequencing and Optical Genome Mapping in Molecularly Unsolved Cases of Duchenne Muscular Dystrophy: Identification of a Causative X-Chromosomal Inversion Disrupting the DMD 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 DMD 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 DMD 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 DMD 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 DMD 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 dmd gene |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10572545/ https://www.ncbi.nlm.nih.gov/pubmed/37834164 http://dx.doi.org/10.3390/ijms241914716 |
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