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 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.

Duchenne expert physician perspectives on Duchenne newborn screening and early Duchenne care

“…The physicians were asked to respond with very discrete answers to questions that are actually complex. For example, it is possible that some physicians would support DMD NBS only for males or only specifically for the variants that are eligible for exon skipping therapies (Beckers et al, 2021), or that they might consider corticosteroids in a child who is 18 months with severe delays but wait until 3 years of age in a child with more typical development.…”

Diagnostic experiences of Duchenne families and their preferences for newborn screening: A mixed‐methods study

“…Several NBS pilots for Duchenne are underway or have recently been completed, (Parad, Sheldon, & Bhattacharjee, 2021 ; Wynn et al, 2022 ) and a nomination package to include Duchenne on the RUSP is in preparation. Screening tests are highly sensitive to detect variants of Duchenne for which there are current therapies (Beckers et al, 2021 ). In the absence of NBS, many patients with Duchenne (as well as those with Becker, a related but milder form of muscular dystrophy) experience diagnostic odysseys which have spillover effects on the family including causing psychosocial distress, financial burdens, and quality of life.…”

Large scale population screening for Duchenne muscular dystrophy—Predictable and unpredictable challenges

“…Another important point to consider is that, due to novel therapeutic options, newborn screening for DMD is considered a beneficial approach by many experts, and a first test for such screening was authorized by the FDA in December 2019. [33][34][35][36] Hence, the issue of presymptomatic screening for dystrophinopathies is already an accepted concept.…”