Abstract

BackgroundBetween 8% and 22% of female carriers of DMD mutations exhibit clinical symptoms of variable severity. Development of symptoms in DMD mutation carriers without chromosomal rearrangements has been attributed to skewed X-chromosome inactivation (XCI) favouring predominant expression of the DMD mutant allele. However the prognostic use of XCI analysis is controversial. We aimed to evaluate the correlation between X-chromosome inactivation and development of clinical symptoms in a series of symptomatic female carriers of dystrophinopathy.MethodsWe reviewed the clinical, pathological and genetic features of twenty-four symptomatic carriers covering a wide spectrum of clinical phenotypes. DMD gene analysis was performed using MLPA and whole gene sequencing in blood DNA and muscle cDNA. Blood and muscle DNA was used for X-chromosome inactivation (XCI) analysis thought the AR methylation assay in symptomatic carriers and their female relatives, asymptomatic carriers as well as non-carrier females.ResultsSymptomatic carriers exhibited 49.2% more skewed XCI profiles than asymptomatic carriers. The extent of XCI skewing in blood tended to increase in line with the severity of muscle symptoms. Skewed XCI patterns were found in at least one first-degree female relative in 78.6% of symptomatic carrier families. No mutations altering XCI in the XIST gene promoter were found.ConclusionsSkewed XCI is in many cases familial inherited. The extent of XCI skewing is related to phenotype severity. However, the assessment of XCI by means of the AR methylation assay has a poor prognostic value, probably because the methylation status of the AR gene in muscle may not reflect in all cases the methylation status of the DMD gene.

Highlights

  • Between 8% and 22% of female carriers of Duchenne muscular dystrophy (DMD) mutations exhibit clinical symptoms of variable severity

  • In this study we aimed to investigate the prognostic value of X-chromosome inactivation in a large series of dystrophinopathy affected females presenting with a wide spectrum of clinical phenotypes

  • Clinical presentation From a total of 344 female carriers of DMD mutations we identified 24 (7%) patients from 23 unrelated families who presented symptoms associated with dystrophinopathy

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Summary

Introduction

Between 8% and 22% of female carriers of DMD mutations exhibit clinical symptoms of variable severity. Development of symptoms in DMD mutation carriers without chromosomal rearrangements has been attributed to skewed X-chromosome inactivation (XCI) favouring predominant expression of the DMD mutant allele. We aimed to evaluate the correlation between X-chromosome inactivation and development of clinical symptoms in a series of symptomatic female carriers of dystrophinopathy. The dystrophinopathies are a group of X-linked muscle diseases caused by mutations in the DMD gene. Clinical phenotypes vary from asymptomatic high CK levels and cramps to severe progressive skeletal and cardiac muscle disorders such as Duchenne (DMD) and Becker (BMD) muscular dystrophies, and X-linked dilated cardiomyopathy (XLCM) [1]. The majority of DMD patients carry truncating mutations while BMD patients usually carry in-frame mutations allowing the expression of semi-functional dystrophins [1,5]

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