Newborn screening of duchenne muscular dystrophy specifically targeting deletions amenable to exon-skipping therapy

Abstract Duchenne Muscular Dystrophy (DMD) is a lethal progressive muscle-wasting disease. New treatment strategies relying on DMD gene exon-skipping therapy have recently been approved and about 30% of patients could be amenable to exon 51, 53 or 45 skipping. We evaluated the spectrum of deletions...

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Autores principales:	Pablo Beckers, Jean-Hubert Caberg, Vinciane Dideberg, Tamara Dangouloff, Johan T. den Dunnen, Vincent Bours, Laurent Servais, François Boemer
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/27dddf18d89948a6a54653f693dce78e
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spelling	oai:doaj.org-article:27dddf18d89948a6a54653f693dce78e2021-12-02T10:44:14ZNewborn screening of duchenne muscular dystrophy specifically targeting deletions amenable to exon-skipping therapy10.1038/s41598-021-82725-z2045-2322https://doaj.org/article/27dddf18d89948a6a54653f693dce78e2021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-82725-zhttps://doaj.org/toc/2045-2322Abstract Duchenne Muscular Dystrophy (DMD) is a lethal progressive muscle-wasting disease. New treatment strategies relying on DMD gene exon-skipping therapy have recently been approved and about 30% of patients could be amenable to exon 51, 53 or 45 skipping. We evaluated the spectrum of deletions reported in DMD registries, and designed a method to screen newborns and identify DMD deletions amenable to exon 51, 53 and 45 skipping. We developed a multiplex qPCR assay identifying hemi(homo)-zygotic deletions of the flanking exons of these therapeutic targets in DMD exons (i.e. exons 44, 46, 50, 52 and 54). We conducted an evaluation of our new method in 51 male patients with a DMD phenotype, 50 female carriers of a DMD deletion and 19 controls. Studies were performed on dried blood spots with patient’s consent. We analyzed qPCR amplification curves of controls, carriers, and DMD patients to discern the presence or the absence of the target exons. Analysis of the exons flanking the exon-skipping targets permitted the identification of patients that could benefit from exon-skipping. All samples were correctly genotyped, with either presence or absence of amplification of the target exon. This proof-of-concept study demonstrates that this new assay is a highly sensitive method to identify DMD patients carrying deletions that are rescuable by exon-skipping treatment. The method is easily scalable to population-based screening. This targeted screening approach could address the new management paradigm in DMD, and could help to optimize the beneficial therapeutic effect of DMD therapies by permitting pre-symptomatic care.Pablo BeckersJean-Hubert CabergVinciane DidebergTamara DangouloffJohan T. den DunnenVincent BoursLaurent ServaisFrançois BoemerNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-9 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Pablo Beckers Jean-Hubert Caberg Vinciane Dideberg Tamara Dangouloff Johan T. den Dunnen Vincent Bours Laurent Servais François Boemer Newborn screening of duchenne muscular dystrophy specifically targeting deletions amenable to exon-skipping therapy
description	Abstract Duchenne Muscular Dystrophy (DMD) is a lethal progressive muscle-wasting disease. New treatment strategies relying on DMD gene exon-skipping therapy have recently been approved and about 30% of patients could be amenable to exon 51, 53 or 45 skipping. We evaluated the spectrum of deletions reported in DMD registries, and designed a method to screen newborns and identify DMD deletions amenable to exon 51, 53 and 45 skipping. We developed a multiplex qPCR assay identifying hemi(homo)-zygotic deletions of the flanking exons of these therapeutic targets in DMD exons (i.e. exons 44, 46, 50, 52 and 54). We conducted an evaluation of our new method in 51 male patients with a DMD phenotype, 50 female carriers of a DMD deletion and 19 controls. Studies were performed on dried blood spots with patient’s consent. We analyzed qPCR amplification curves of controls, carriers, and DMD patients to discern the presence or the absence of the target exons. Analysis of the exons flanking the exon-skipping targets permitted the identification of patients that could benefit from exon-skipping. All samples were correctly genotyped, with either presence or absence of amplification of the target exon. This proof-of-concept study demonstrates that this new assay is a highly sensitive method to identify DMD patients carrying deletions that are rescuable by exon-skipping treatment. The method is easily scalable to population-based screening. This targeted screening approach could address the new management paradigm in DMD, and could help to optimize the beneficial therapeutic effect of DMD therapies by permitting pre-symptomatic care.
format	article
author	Pablo Beckers Jean-Hubert Caberg Vinciane Dideberg Tamara Dangouloff Johan T. den Dunnen Vincent Bours Laurent Servais François Boemer
author_facet	Pablo Beckers Jean-Hubert Caberg Vinciane Dideberg Tamara Dangouloff Johan T. den Dunnen Vincent Bours Laurent Servais François Boemer
author_sort	Pablo Beckers
title	Newborn screening of duchenne muscular dystrophy specifically targeting deletions amenable to exon-skipping therapy
title_short	Newborn screening of duchenne muscular dystrophy specifically targeting deletions amenable to exon-skipping therapy
title_full	Newborn screening of duchenne muscular dystrophy specifically targeting deletions amenable to exon-skipping therapy
title_fullStr	Newborn screening of duchenne muscular dystrophy specifically targeting deletions amenable to exon-skipping therapy
title_full_unstemmed	Newborn screening of duchenne muscular dystrophy specifically targeting deletions amenable to exon-skipping therapy
title_sort	newborn screening of duchenne muscular dystrophy specifically targeting deletions amenable to exon-skipping therapy
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/27dddf18d89948a6a54653f693dce78e
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Newborn screening of duchenne muscular dystrophy specifically targeting deletions amenable to exon-skipping therapy

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