title: Xq28 duplication including MECP2 in six unreported affected females: what can we learn for diagnosis and genetic counselling?
abstract: Duplication of the Xq28 region, involving MECP2 (dupMECP2), has been primarily described in males with severe developmental delay, spasticity, epilepsy, stereotyped movements and recurrent infections. Carrier mothers are usually asymptomatic with an extremely skewed X chromosome inactivation (XCI) pattern. We report a series of six novel symptomatic females carrying a de novo interstitial dupMECP2, and review the 14 symptomatic females reported to date, with the aim to further delineate their phenotype and give clues for genetic counselling. One patient was adopted and among the other 19 patients, seven (37%) had inherited their duplication from their mother, including three mildly (XCI: 70/30, 63/37, 100/0 in blood and random in saliva), one moderately (XCI: random) and three severely (XCI: uninformative and 88/12) affected patients. After combining our data with data from the literature, we could not show a correlation between XCI in the blood or duplication size and the severity of the phenotype, or explain the presence of a phenotype in these females. These findings confirm that an abnormal phenotype, even severe, can be a rare event in females born to asymptomatic carrier mothers, making genetic counselling difficult in couples at risk in terms of prognosis, in particular in prenatal cases.
authors.affiliation: FHU TRANSLAD, Centre de Référence Maladies Rares «Anomalies du Développement et Syndromes Malformatifs» de l'Est, Centre de Génétique, CHU de Dijon, Dijon, France.|Service de Génétique Médicale, Institut de Génétique Médicale d'Alsace (IGMA), Centre de Référence Maladies Rares «Anomalies du Développement et Syndromes Malformatifs» de l'Est, Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, Strasbourg, France.
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authors.forename: R
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authors.lastname: Touraine
authors.affiliation: Service de Génétique Clinique Chromosomique et Moléculaire, CHU de Saint-Etienne, Saint-Étienne, France.
authors.forename: F
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authors.forename: W
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authors.affiliation: AP-HP, Laboratoire de Génétique et Biologie Moléculaires, HU Paris Centre, Site Cochin, France; Université Paris Descartes, Institut Cochin, INSERM U1016, Paris, France.
authors.forename: T
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authors.affiliation: Service de Génétique et Embryologie Médicales, CHU Paris Est - Hôpital d'Enfants Armand-Trousseau, Paris, France.
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authors.affiliation: Service de Cytogénétique, CHU de Dijon, Dijon, France.
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authors.affiliation: Service de Cytogénétique, CHU de Dijon, Dijon, France.
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authors.affiliation: Service de Génétique et Inserm U1079, Centre Normand de Génomique Médicale et Médecine Personnalisée, CHU de Rouen, Inserm et Université de Rouen, Rouen, France.
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authors.affiliation: FHU TRANSLAD, Centre de Référence Maladies Rares «Anomalies du Développement et Syndromes Malformatifs» de l'Est, Centre de Génétique, CHU de Dijon, Dijon, France.|GAD, EA4271, Génétique et Anomalies du Développement, Université de Bourgogne, Dijon, France.
authors.forename: J
authors.identifier: http://orcid.org/0000-0001-9271-3961
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authors.affiliation: FHU TRANSLAD, Centre de Référence Maladies Rares «Anomalies du Développement et Syndromes Malformatifs» de l'Est, Centre de Génétique, CHU de Dijon, Dijon, France.|GAD, EA4271, Génétique et Anomalies du Développement, Université de Bourgogne, Dijon, France.
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authors.affiliation: EPICIME-CIC 1407 de Lyon, Inserm, Service de Pharmacologie Clinique, CHU-Lyon, Bron, France.
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authors.affiliation: FHU TRANSLAD, Centre de Référence Maladies Rares «Anomalies du Développement et Syndromes Malformatifs» de l'Est, Centre de Génétique, CHU de Dijon, Dijon, France.|GAD, EA4271, Génétique et Anomalies du Développement, Université de Bourgogne, Dijon, France.
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mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D041321:Chromosomes, Human, X / Q000235:genetics; D005260:Female; D020440:Gene Duplication; D005817:Genetic Counseling; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics* / Q000503:physiopathology; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype
chemical_list: C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2
keywords: MECP2 duplication syndrome; MECP2 gene; X chromosome inactivation; Xq28 duplication; affected females; genetic counselling