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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,...

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Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
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.
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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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