An Integrated Transcriptomics and Genomics Approach Detects an X/Autosome Translocation in a Female with Duchenne Muscular Dystrophy
Segarra Casas, Alba (Institut de Recerca Sant Pau)
Yépez, Vicente A. (Technical University of Munich)
Demidov, German (Universitätsklinikum Tübingen-Institut für Medizinische Genetik und angewandte Genomik)
Laurie, Steven (Centre Nacional d'Anàlisi Genòmica)
Esteve-Codina, Anna (Universitat de Barcelona)
Gagneur, Julien (Helmholtz Center Munich)
Parkhurst, Yolande (Newcastle Upon Tyne Hospitals NHS Trust (Newcastle, Regne Unit))
Muni-Lofra, Robert (Newcastle University and Newcastle Hospitals NHS Foundation Trust)
Harris, Elizabeth (Newcastle University and Newcastle Hospitals NHS Foundation Trust)
Marini-Bettolo, Chiara (Newcastle University and Newcastle Hospitals NHS Foundation Trust)
Straub, Volker (Newcastle University and Newcastle Hospitals NHS Foundation Trust)
Töpf, Ana (Newcastle University and Newcastle Hospitals NHS Foundation Trust)
Universitat Autònoma de Barcelona

Data:	2024
Resum:	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.
Ajuts:	European Commission 779257 Ministerio de Universidades FPU20/06692 Ministerio de Universidades EST23/00463
Nota:	Altres ajuts: This study was also funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) via the project NFDI 1/1 \u201CGHGA\u2014German Human Genome-Phenome Archive\u201D (#441914366 to VAY and JG).
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	DMD ; Duchenne muscular dystrophy ; Female carrier ; Genetic diagnosis ; RNA sequencing ; Translocation ; Whole genome sequencing
Publicat a:	International journal of molecular sciences, Vol. 25 Núm. 14 (july 2024) , p. 7793, ISSN 1422-0067

DOI: 10.3390/ijms25147793
PMID: 39063034

12 p, 1.6 MB

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