title: Structural variation in Xq28: MECP2 duplications in 1% of patients with unexplained XLMR and in 2% of male patients with severe encephalopathy.
abstract: Duplications in Xq28 involving MECP2 have been described in patients with severe mental retardation, infantile hypotonia, progressive spasticity, and recurrent infections. However, it is not yet clear to what extent these and accompanying symptoms may vary. In addition, the frequency of Xq28 duplications including MECP2 has yet to be determined in patients with unexplained X-linked mental retardation and (fe)males with severe encephalopathy. In this study, we used multiplex ligation-dependent probe amplification to screen Xq28 including MECP2 for deletions and duplications in these patient cohorts. In the group of 283 patients with X-linked mental retardation, we identified three Xq28 duplications including MECP2, which suggests that approximately 1% of unexplained X-linked mental retardation may be caused by MECP2 duplications. In addition, we found three additional MECP2 duplications in 134 male patients with mental retardation and severe, mostly progressive, neurological symptoms, indicating that the mutation frequency could be as high as 2% in this group of patients. In 329 female patients, no Xq28 duplications were detected. In total, we assessed 13 male patients with a MECP2 duplication from six unrelated families. Moderate to severe mental retardation and childhood hypotonia was noted in all patients. The majority of the patients also presented with absent speech, seizures, and progressive spasticity as well as ataxia or an ataxic gait and cerebral atrophy, two previously unreported symptoms. We propose to implement DNA copy number testing for MECP2 in the current diagnostic testing in all males with moderate to severe mental retardation accompanied by (progressive) neurological symptoms.
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Dorien
authors.initials: D
authors.lastname: Lugtenberg
authors.forename: Tjitske
authors.initials: T
authors.lastname: Kleefstra
authors.forename: Astrid R
authors.initials: AR
authors.lastname: Oudakker
authors.forename: Willy M
authors.initials: WM
authors.lastname: Nillesen
authors.forename: Helger G
authors.initials: HG
authors.lastname: Yntema
authors.forename: Andreas
authors.initials: A
authors.lastname: Tzschach
authors.forename: Martine
authors.initials: M
authors.lastname: Raynaud
authors.forename: Dietz
authors.initials: D
authors.lastname: Rating
authors.forename: Hubert
authors.initials: H
authors.lastname: Journel
authors.forename: Jamel
authors.initials: J
authors.lastname: Chelly
authors.forename: Cyril
authors.initials: C
authors.lastname: Goizet
authors.forename: Didier
authors.initials: D
authors.lastname: Lacombe
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Pedespan
authors.forename: Bernard
authors.initials: B
authors.lastname: Echenne
authors.forename: Gholamali
authors.initials: G
authors.lastname: Tariverdian
authors.forename: Declan
authors.initials: D
authors.lastname: O'Rourke
authors.forename: Mary D
authors.initials: MD
authors.lastname: King
authors.forename: Andrew
authors.initials: A
authors.lastname: Green
authors.forename: Margriet
authors.initials: M
authors.lastname: van Kogelenberg
authors.forename: Hilde
authors.initials: H
authors.lastname: Van Esch
authors.forename: Jozef
authors.initials: J
authors.lastname: Gecz
authors.forename: Ben C J
authors.initials: BC
authors.lastname: Hamel
authors.forename: Hans
authors.initials: H
authors.lastname: van Bokhoven
authors.forename: Arjan P M
authors.initials: AP
authors.lastname: de Brouwer
mesh_terms: D000293:Adolescent; D001927:Brain Diseases / Q000235:genetics* / Q000378:metabolism; D002648:Child; D041321:Chromosomes, Human, X / Q000235:genetics*; D015331:Cohort Studies; D005190:Family; D005260:Female; D020440:Gene Duplication; D014644:Genetic Variation; D006801:Humans; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics*; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D055815:Young Adult
chemical_list: C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2