Prognostic significance of ACTN3 genotype in Duchenne muscular dystrophy: Findings from an Argentine patient cohort

A wide phenotypic spectrum exists among DMD patients, with genetic modifiers seen as a putative cause of this variability. The main aim was to evaluate the effect of 4 genetic modifiers and the location of DMD variants on disease severity in a DMD Argentine cohort. A secondary objective was to provide a summary of the current state of knowledge and association of the tested loci with DMD's phenotype. Two groups of patients with extreme phenotypes (Severe/Mild) were defined based on the age at loss of ambulation. SNVs in SPP1, LTBP4, CD40, and ACTN3 were genotyped, and their distribution was compared between groups using Chi-square or Fisher exact tests. Concurrent effects with glucocorticoids treatment, DMD mutation location (proximal/distal) and the other loci were evaluated by multivariate logistic regression. Additionally, we performed a systematic literature review to summarize and interpret the impact of modifiers on various DMD traits. ACTN3-rs1815739 was the only modifier loci of DMD progression in our cohort. A concurrent damaging effect between DMD mutation and ACTN3 was detected, identifying a possible interaction between distal variants and ACTN3 TT-genotype that need to be validated in a larger cohort. The systematic review showed agreement in the results when significant differences were reported. The employment of extreme DMD phenotypic groups was an innovative approach for identifying risk loci for disease severity. The interaction between DMD mutation location and ACTN3, if confirmed, could help to avoid confounding elements in assembling study cohorts for clinical trials. Finally, this report's major highlight is being the first study conducted on an Argentine and Latin-American population.