An Integrated Transcriptomics and Genomics Approach Detects an X/Autosome Translocation in a Female with Duchenne Muscular Dystrophy
Por:
Segarra-Casas, A, Yepez, VA, Demidov, G, Laurie, S, Esteve-Codina, A, Gagneur, J, Parkhurst, Y, Muni-Lofra, R, Harris, E, Marini-Bettolo, C, Straub, V, Töpf, A
Publicada:
1 jul 2024
Resumen:
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.
Filiaciones:
Segarra-Casas, A:
Newcastle Univ, Translat & Clin Res Inst, John Walton Muscular Dystrophy Res Ctr, Newcastle Upon Tyne NE1 3BZ, England
Newcastle Hosp NHS Fdn Trust, Newcastle Upon Tyne NE1 3BZ, England
Univ Autonoma Barcelona, Hosp St Creu & Santa Pau, Inst Recerca St Pau IR SANT PAU, Genet & Microbiol Dept,Genet Dept, Barcelona 08041, Spain
Yepez, VA:
Tech Univ Munich, Sch Computat Informat & Technol, D-85748 Garching, Germany
Demidov, G:
Univ Klinikum Tubingen, Inst Med Genet & Angew Genom, D-72076 Tubingen, Germany
Laurie, S:
Ctr Nacl Anal Genom CNAG, Barcelona 08028, Spain
Esteve-Codina, A:
Ctr Nacl Anal Genom CNAG, Barcelona 08028, Spain
Univ Barcelona UB, Barcelona 08007, Spain
Gagneur, J:
Tech Univ Munich, Sch Computat Informat & Technol, D-85748 Garching, Germany
Tech Univ Munich, Inst Human Genet, Sch Med, D-81675 Munich, Germany
Helmholtz Ctr Munich, Computat Hlth Ctr, D-85764 Neuherberg, Germany
Parkhurst, Y:
Newcastle Tyne Hosp NHS Fdn Trust, Muscle Immunoanalysis Unit, Newcastle Upon Tyne NE7 7DN, England
Muni-Lofra, R:
Newcastle Univ, Translat & Clin Res Inst, John Walton Muscular Dystrophy Res Ctr, Newcastle Upon Tyne NE1 3BZ, England
Newcastle Hosp NHS Fdn Trust, Newcastle Upon Tyne NE1 3BZ, England
Harris, E:
Newcastle Univ, Translat & Clin Res Inst, John Walton Muscular Dystrophy Res Ctr, Newcastle Upon Tyne NE1 3BZ, England
Newcastle Hosp NHS Fdn Trust, Newcastle Upon Tyne NE1 3BZ, England
Marini-Bettolo, C:
Newcastle Univ, Translat & Clin Res Inst, John Walton Muscular Dystrophy Res Ctr, Newcastle Upon Tyne NE1 3BZ, England
Newcastle Hosp NHS Fdn Trust, Newcastle Upon Tyne NE1 3BZ, England
Straub, V:
Newcastle Univ, Translat & Clin Res Inst, John Walton Muscular Dystrophy Res Ctr, Newcastle Upon Tyne NE1 3BZ, England
Newcastle Hosp NHS Fdn Trust, Newcastle Upon Tyne NE1 3BZ, England
Töpf, A:
Newcastle Univ, Translat & Clin Res Inst, John Walton Muscular Dystrophy Res Ctr, Newcastle Upon Tyne NE1 3BZ, England
Newcastle Hosp NHS Fdn Trust, Newcastle Upon Tyne NE1 3BZ, England
Green Published, gold
|