Structural variation in Xq28: MECP2 duplications in 1% of patients with unexplained XLMR and in 2% of male patients with severe encephalopathy.
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.
Lugtenberg
Dorien
D
Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Kleefstra
Tjitske
T
Oudakker
Astrid R
AR
Nillesen
Willy M
WM
Yntema
Helger G
HG
Tzschach
Andreas
A
Raynaud
Martine
M
Rating
Dietz
D
Journel
Hubert
H
Chelly
Jamel
J
Goizet
Cyril
C
Lacombe
Didier
D
Pedespan
Jean-Michel
JM
Echenne
Bernard
B
Tariverdian
Gholamali
G
O'Rourke
Declan
D
King
Mary D
MD
Green
Andrew
A
van Kogelenberg
Margriet
M
Van Esch
Hilde
H
Gecz
Jozef
J
Hamel
Ben C J
BC
van Bokhoven
Hans
H
de Brouwer
Arjan P M
AP
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
C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2