Genetic and clinical specificity of 26 symptomatic carriers for dystrophinopathies at pediatric age This article has been corrected since online publication and a corrigendum is also printed in this issue

The molecular basis underlying the clinical variability in symptomatic Duchenne muscular dystrophy (DMD) carriers are still tobe precised. We report 26 cases of early symptomatic DMD carriers followed in the French neuromuscular network. Clinicalpresentation, muscular histological analysis and type of gene mutation, as well as X-chromosome inactivation (XCI) patternsusing DNA extracted from peripheral blood or muscle are detailed. The initial symptoms were significant weakness (88%) orexercise intolerance (27%). Clinical severity varied from a Duchenne-like progression to a very mild Becker-like phenotype.Cardiac dysfunction was present in 19% of the cases. Cognitive impairment was worthy of notice, as 27% of the carriers areconcerned. The muscular analysis was always contributive, revealing muscular dystrophy (83%), mosaic in immunostaining(81%) and dystrophin abnormalities in western blot analysis (84%). In all, 73% had exonic deletions or duplications and 27%had point mutations. XCI pattern was biased in 62% of the cases. In conclusion, we report the largest series of manifestingDMD carriers at pediatric age and show that exercise intolerance and cognitive impairment may reveal symptomatic DMDcarriers. The complete histological and immunohistological study of the muscle is the key of the diagnosis leading to thedystrophin gene analysis. Our study shows also that cognitive impairment in symptomatic DMD carriers is associated withmutations in the distal part of the DMD gene. XCI study does not fully explain the mechanisms as well as the wide spectrum ofclinical phenotype, though a clear correlation between the severity of the phenotype and inactivation bias was observed.European Journal of Human Genetics (2013) 21, 855–863; doi:10.1038/ejhg.2012.269; published online 9 January 2013Keywords: dystrophin; female carrier; X inactivationINTRODUCTIONDuchenne muscular dystrophy (DMD) has always been extensivelydescribed in its clinical presentation, evolution and severity.