Recurrent infections, hypotonia, and mental retardation caused by duplication of MECP2 and adjacent region in Xq28.
OBJECTIVE
Our goal was to describe the neurologic and clinical features of affected males from families with X-linked patterns of severe mental retardation, hypotonia, recurrent respiratory infection, and microduplication of Xq28 that consistently includes the MECP2 (methyl-CpG binding protein 2) gene.


METHODS
To identify duplications, multiplex ligation-dependent probe amplification of the MECP2 gene was performed on male probands from families with X-linked mental retardation. The males either had linkage to Xq28 or had a phenotype consistent with previous reports involving Xq28 functional disomy. After detection of a duplication of MECP2, additional family members were tested to confirm the MECP2 duplication segregated with the affected phenotype, and X-inactivation studies were performed on carrier females.


RESULTS
Six families with multiple affected males having MECP2 duplications were identified by multiplex ligation-dependent probe amplification, and the carrier mothers were subsequently shown to have highly skewed X inactivation. In 5 of 6 families, the microduplication extended proximally to include the L1 cell adhesion molecule gene. The primary clinical features associated with this microduplication are infantile hypotonia, recurrent respiratory infection, severe mental retardation, absence of speech development, seizures, and spasticity.


CONCLUSIONS
Although many of the phenotypic features of our patients are rather nonspecific in cohorts of individuals with syndromic and nonsyndromic mental retardation, the proneness to infection is quite striking because the patients had normal growth and were not physically debilitated. Although the etiology of the infections is not understood, we recommend considering MECP2 dosage studies and a genetics referral in individuals with severe developmental delay and neurologic findings, especially when a history of recurrent respiratory ailments has been documented.
Friez
Michael J
MJ
Greenwood Genetic Center, 1 Gregor Mendel Circle, Greenwood, SC 29646, USA. friez@ggc.org
Jones
Julie R
JR
Clarkson
Katie
K
Lubs
Herbert
H
Abuelo
Dianne
D
Bier
Jo-Ann Blaymore
JA
Pai
Shashidhar
S
Simensen
Richard
R
Williams
Charles
C
Giampietro
Philip F
PF
Schwartz
Charles E
CE
Stevenson
Roger E
RE
D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D041321:Chromosomes, Human, X / Q000235:genetics*; D005260:Female; D020440:Gene Duplication; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D009123:Muscle Hypotonia / Q000235:genetics*; D010375:Pedigree; D012008:Recurrence; D012141:Respiratory Tract Infections / Q000235:genetics*
C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2