title: Prognostic value of X-chromosome inactivation in symptomatic female carriers of dystrophinopathy.
abstract: BACKGROUND
  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. 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.
  
  
  METHODS
  We 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.
  
  
  RESULTS
  Symptomatic 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.
  
  
  CONCLUSIONS
  Skewed 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.
authors.affiliation: Servei de Genètica, Hospital de la Santa Creu i Sant Pau and CIBERER, Barcelona, Spain.
authors.forename: Jonàs
authors.initials: J
authors.lastname: Juan-Mateu
authors.forename: Maria José
authors.initials: MJ
authors.lastname: Rodríguez
authors.forename: Andrés
authors.initials: A
authors.lastname: Nascimento
authors.forename: Cecilia
authors.initials: C
authors.lastname: Jiménez-Mallebrera
authors.forename: Lidia
authors.initials: L
authors.lastname: González-Quereda
authors.forename: Eloy
authors.initials: E
authors.lastname: Rivas
authors.forename: Carmen
authors.initials: C
authors.lastname: Paradas
authors.forename: Marcos
authors.initials: M
authors.lastname: Madruga
authors.forename: Pedro
authors.initials: P
authors.lastname: Sánchez-Ayaso
authors.forename: Cristina
authors.initials: C
authors.lastname: Jou
authors.forename: Laura
authors.initials: L
authors.lastname: González-Mera
authors.forename: Francina
authors.initials: F
authors.lastname: Munell
authors.forename: Manuel
authors.initials: M
authors.lastname: Roig-Quilis
authors.forename: Maria
authors.initials: M
authors.lastname: Rabasa
authors.forename: Aurelio
authors.initials: A
authors.lastname: Hernández-Lain
authors.forename: Jorge
authors.initials: J
authors.lastname: Díaz-Manera
authors.forename: Eduard
authors.initials: E
authors.lastname: Gallardo
authors.forename: Jordi
authors.initials: J
authors.lastname: Pascual
authors.forename: Edgard
authors.initials: E
authors.lastname: Verdura
authors.forename: Jaume
authors.initials: J
authors.lastname: Colomer
authors.forename: Montserrat
authors.initials: M
authors.lastname: Baiget
authors.forename: Montse
authors.initials: M
authors.lastname: Olivé
authors.forename: Pia
authors.initials: P
authors.lastname: Gallano
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001706:Biopsy; D002648:Child; D002675:Child, Preschool; D016189:Dystrophin / Q000235:genetics*; D005260:Female; D006580:Genetic Carrier Screening; D006801:Humans; D018482:Muscle, Skeletal / Q000473:pathology; D009136:Muscular Dystrophies / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D011379:Prognosis; D011401:Promoter Regions, Genetic; D049951:X Chromosome Inactivation; D055815:Young Adult
chemical_list: C484258:DMD protein, human; D016189:Dystrophin