Abstract
BackgroundDuchenne muscular dystrophy (DMD) is a rare and severe X-linked muscular dystrophy in which the standard of care with variable outcome, also due to different drug response, is chronic off-label treatment with corticosteroids (CS). In order to search for SNP biomarkers for corticosteroid responsiveness, we genotyped variants across 205 DMD-related genes in patients with differential response to steroid treatment.Methods and FindingsWe enrolled a total of 228 DMD patients with identified dystrophin mutations, 78 of these patients have been under corticosteroid treatment for at least 5 years. DMD patients were defined as high responders (HR) if they had maintained the ability to walk after 15 years of age and low responders (LR) for those who had lost ambulation before the age of 10 despite corticosteroid therapy. Based on interactome mapping, we prioritized 205 genes and sequenced them in 21 DMD patients (discovery cohort or DiC = 21). We identified 43 SNPs that discriminate between HR and LR. Discriminant Analysis of Principal Components (DAPC) prioritized 2 response-associated SNPs in the TNFRSF10A gene. Validation of this genotype was done in two additional larger cohorts composed of 46 DMD patients on corticosteroid therapy (validation cohorts or VaC1), and 150 non ambulant DMD patients and never treated with corticosteroids (VaC2). SNP analysis in all validation cohorts (N = 207) showed that the CT haplotype is significantly associated with HR DMDs confirming the discovery results.ConclusionWe have shown that TNFRSF10A CT haplotype correlates with corticosteroid response in DMD patients and propose it as an exploratory CS response biomarker.
Highlights
Duchenne muscular dystrophy (DMD, OMIM ∗310200) is a rare hereditary disease due to mutations in the dystrophin (DMD) gene, which maps to the X-chromosome (Xp21.1), and affects 1 in 5,000 newborn males
We sequenced the 205 prioritized genes by SOLiD sequencing in 21 DMD patients belonging to the discovery cohort (DiC) and SNP calling and retrieved a total of 1714 SNPs exonic variants in all the lanes
SPP1 and LTBP4 are validated genetic modifiers linked to loss of ambulation (LoA) in steroid-treated boys (Flanigan et al, 2013; Bello et al, 2015; van den Bergen et al, 2015), while promising new biomarkers, as ACTN3 and CD40, or THBS1 as locus modifier, were recently identified as associated with LoA in DMD boys (Bello et al, 2016; Hogarth et al, 2017; Weiss et al, 2018)
Summary
Duchenne muscular dystrophy (DMD, OMIM ∗310200) is a rare hereditary disease due to mutations in the dystrophin (DMD) gene, which maps to the X-chromosome (Xp21.1), and affects 1 in 5,000 newborn males. It is characterized by the almost complete absence of the dystrophin protein (DYS) in muscle fibers, which causes progressive muscle damage leading to death in the first 3 decades of life (Goemans and Buyse, 2014). Duchenne muscular dystrophy (DMD) is a rare and severe X-linked muscular dystrophy in which the standard of care with variable outcome, due to different drug response, is chronic off-label treatment with corticosteroids (CS). In order to search for SNP biomarkers for corticosteroid responsiveness, we genotyped variants across 205 DMD-related genes in patients with differential response to steroid treatment
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