9f3d9a195b5f4ac8f1ab86d5443c1c9a 299784.pdf b0e7adadc2774b4f9f1afdc93afa2f9f27caf6fa 299784.pdf b44a5df867faf939c21d66904b2fc5e5874ac11344fd623aef693c640881d63d 299784.pdf Title: An Integrated Transcriptomics and Genomics Approach Detects an X/Autosome Translocation in a Female with Duchenne Muscular Dystrophy Subject: Duchenne and Becker muscular dystrophies, caused by pathogenic variants in DMD, are the most common inherited neuromuscular conditions in childhood. These diseases follow an X-linked recessive inheritance pattern, and mainly males are affected. The most prevalent pathogenic variants in the DMD gene are copy number variants (CNVs), and most patients achieve their genetic diagnosis through Multiplex Ligation-dependent Probe Amplification (MLPA) or exome sequencing. Here, we investigated a female patient presenting with muscular dystrophy who remained genetically undiagnosed after MLPA and exome sequencing. RNA sequencing (RNAseq) from the patient’s muscle biopsy identified an 85% reduction in DMD expression compared to 116 muscle samples included in the cohort. A de novo balanced translocation between chromosome 17 and the X chromosome (t(X;17)(p21.1;q23.2)) disrupting the DMD and BCAS3 genes was identified through trio whole genome sequencing (WGS). The combined analysis of RNAseq and WGS played a crucial role in the detection and characterisation of the disease-causing variant in this patient, who had been undiagnosed for over two decades. This case illustrates the diagnostic odyssey of female DMD patients with complex structural variants that are not detected by current panel or exome sequencing analysis. Keywords: Duchenne muscular dystrophy; female carrier; DMD; genetic diagnosis; RNA sequencing; whole genome sequencing; translocation Author: Alba Segarra-Casas, Vicente A. Yépez, German Demidov, Steven Laurie, Anna Esteve-Codina, Julien Gagneur, Yolande Parkhurst, Robert Muni-Lofra, Elizabeth Harris, Chiara Marini-Bettolo, Volker Straub and Ana Töpf Creator: LaTeX with hyperref Producer: pdfTeX-1.40.25 CreationDate: Wed Jul 24 10:09:27 2024 CEST ModDate: Wed Jul 24 10:12:34 2024 CEST Custom Metadata: no Metadata Stream: no Tagged: no UserProperties: no Suspects: no Form: none JavaScript: no Pages: 12 Encrypted: no Page size: 595.276 x 841.89 pts (A4) Page rot: 0 File size: 1626828 bytes Optimized: no PDF version: 1.7 name type encoding emb sub uni object ID ------------------------------------ ----------------- ---------------- --- --- --- --------- BTFGED+VnURWPalladioL-Bold Type 1 Custom yes yes yes 10 0 UVCOFK+URWPalladioL-Bold Type 1 Custom yes yes yes 16 0 RMDXUA+URWPalladioL-Roma Type 1 Custom yes yes yes 22 0 YURTAD+URWPalladioL-Ital Type 1 Custom yes yes yes 27 0 OPZDHV+VnURWPalladioL Type 1 Custom yes yes yes 32 0 IRWHZX+TimesNewRomanPSMT Type 1C WinAnsi yes yes no 48 0 CKUPDE+TimesNewRomanPS-BoldItalicMT Type 1C WinAnsi yes yes no 51 0 KNPFEX+EURM10 Type 1 Builtin yes yes yes 71 0 VIWIOF+CMSY10 Type 1 Builtin yes yes yes 83 0 Jhove (Rel. 1.28.0, 2023-05-18) Date: 2024-12-17 02:58:47 CET RepresentationInformation: 299784.pdf ReportingModule: PDF-hul, Rel. 1.12.4 (2023-03-16) LastModified: 2024-12-13 11:51:40 CET Size: 1626828 Format: PDF Version: 1.7 Status: Well-Formed and valid SignatureMatches: PDF-hul MIMEtype: application/pdf PDFMetadata: Objects: 300 FreeObjects: 1 IncrementalUpdates: 0 DocumentCatalog: PageLayout: SinglePage PageMode: UseNone Outlines: Item: Title: Introduction Destination: section.1 Item: Title: Results Destination: section.2 Children: Item: Title: Clinical Presentation Destination: subsection.2.1 Item: Title: Histopathological Findings Destination: subsection.2.2 Item: Title: Routine Genetic Studies Destination: subsection.2.3 Item: Title: Transcriptomics and Whole Genome Sequencing Destination: subsection.2.4 Item: Title: Karyotype Destination: subsection.2.5 Item: Title: Discussion Destination: section.3 Item: Title: Materials and Methods Destination: section.4 Item: Title: References Destination: section.5 Info: Title: An Integrated Transcriptomics and Genomics Approach Detects an X/Autosome Translocation in a Female with Duchenne Muscular Dystrophy Author: Alba Segarra-Casas, Vicente A. Yépez, German Demidov, Steven Laurie, Anna Esteve-Codina, Julien Gagneur, Yolande Parkhurst, Robert Muni-Lofra, Elizabeth Harris, Chiara Marini-Bettolo, Volker Straub and Ana Töpf Subject: Duchenne and Becker muscular dystrophies, caused by pathogenic variants in DMD, are the most common inherited neuromuscular conditions in childhood. These diseases follow an X-linked recessive inheritance pattern, and mainly males are affected. The most prevalent pathogenic variants in the DMD gene are copy number variants (CNVs), and most patients achieve their genetic diagnosis through Multiplex Ligation-dependent Probe Amplification (MLPA) or exome sequencing. Here, we investigated a female patient presenting with muscular dystrophy who remained genetically undiagnosed after MLPA and exome sequencing. RNA sequencing (RNAseq) from the patient’s muscle biopsy identified an 85% reduction in DMD expression compared to 116 muscle samples included in the cohort. A de novo balanced translocation between chromosome 17 and the X chromosome (t(X;17)(p21.1;q23.2)) disrupting the DMD and BCAS3 genes was identified through trio whole genome sequencing (WGS). The combined analysis of RNAseq and WGS played a crucial role in the detection and characterisation of the disease-causing variant in this patient, who had been undiagnosed for over two decades. This case illustrates the diagnostic odyssey of female DMD patients with complex structural variants that are not detected by current panel or exome sequencing analysis. 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