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Prognostic value of X-chromosome inactivation in symptomatic female carriers of dystrophinopathy

Jonàs Juan-Mateu12, Maria José Rodríguez1, Andrés Nascimento3, Cecilia Jiménez-Mallebrera3, Lidia González-Quereda1, Eloy Rivas4, Carmen Paradas5, Marcos Madruga6, Pedro Sánchez-Ayaso7, Cristina Jou8, Laura González-Mera9, Francina Munell10, Manuel Roig-Quilis1011, Maria Rabasa12, Aurelio Hernández-Lain13, Jorge Díaz-Manera14, Eduard Gallardo14, Jordi Pascual15, Edgard Verdura1, Jaume Colomer4, Montserrat Baiget1, Montse Olivé16 and Pia Gallano1*

Author Affiliations

1 Servei de Genètica, Hospital de la Santa Creu i Sant Pau and CIBERER, Barcelona, Spain

2 Universitat de Barcelona (UB), Barcelona, Spain

3 Unitat de Patologia Neuromuscular, Servei de Neurologia, Hospital Sant Joan de Déu, Barcelona, Spain

4 Servicio de Anatomía Patológica, Hospital Universitario Virgen del Rocío, Sevilla, Spain

5 Unidad de Enfermedades Neuromusculares, Servicio de Neurología, Hospital Universitario Virgen del Rocío, Sevilla, Spain

6 Unidad de Neurología Pediátrica, Hospital Universitario Virgen del Rocío, Sevilla, Spain

7 Servicio de Neurología, Hospital General Universitario de Albacete, Albacete, España

8 Servei d’Anatomia Patològica, Hospital Sant Joan de Déu, Barcelona, Spain

9 Servei de Neurologia, Hospital de Viladecans, Barcelona, Spain

10 Institut de Recerca Hospital Universitari Vall d'Hebrón, Barcelona, Spain

11 Secció de Neurología Infantil, Hospital Materno-Infantil, Hospital Universitari Vall d'Hebron, Barcelona, Spain

12 Neurología, Hospital Universitario de Fuenlabrada, Fuenlabrada, Spain

13 Servicio de Neuropatología, Hospital Universitario 12 de Octubre, Madrid, Spain

14 Laboratori de Malalties Neuromusculars, Servei de Neurologia, Hospital de la Santa Creu i Sant Pau, Institut de Recerca de HSCSP, Universitat Autònoma de Barcelona and CIBERNED, Barcelona, Spain

15 Servei de Neurologia, Hospital del Mar and Universitat Autònoma, Barcelona, Spain

16 Institut de Neuropatologia, IDIBELL-Hospital de Bellvitge and CIBERNED, Hospitalet de Llobregat, Catalonia, Spain

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Orphanet Journal of Rare Diseases 2012, 7:82  doi:10.1186/1750-1172-7-82

Published: 23 October 2012



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.


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.


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.


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.

Dystrophin; DMD; Symptomatic carrier; Duchenne muscular dystrophy; Becker muscular dystrophy; X-chromosome inactivation