Structural variation in Xq28: MECP2 duplications in 1% of patients with unexplained XLMR and in 2% of male patients with severe encephalopathy

Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
European journal of human genetics: EJHG (Impact Factor: 4.35). 12/2008; 17(4):444-53. DOI: 10.1038/ejhg.2008.208
Source: PubMed


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.

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    • "Loss-of-function MECP2 mutations had been identified as the cause of Rett syndrome, mainly affecting females [34] and initially thought to be lethal in males [22]. Duplications involving MECP2 have been frequently identified in male patients presenting with a different phenotype from that of Rett syndrome and mainly characterized by severe mental retardation, recurrent respiratory infections, epilepsy, cerebellar degenerative change and progressive encephalopathy [4-6,8,12,14,24]. Whereas the phenotypic effect of MECP2 duplications has already been well documented in males, the clinical implications determined by these rearrangements is still poorly known in females. "
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    ABSTRACT: Xq28 duplications, including MECP2 (methyl CpG-binding protein 2; OMIM 300005), have been identified in approximately 140 male patients presenting with hypotonia, severe developmental delay/intellectual disability, limited or absent speech and ambulation, and recurrent respiratory infections. Female patients with Xq28 duplication have been rarely reported and are usually asymptomatic. Altogether, only fifteen symptomatic females with Xq28 duplications including MECP2 have been reported so far: six of them had interstitial duplications while the remaining had a duplication due to an unbalanced X;autosome translocation. Some of these females present with unspecific mild to moderate intellectual disability whereas a more complex phenotype is reported for females with unbalanced X;autosome translocations. Here we report on the clinical features of three other adolescent to adult female patients with Xq28 interstitial duplications of variable size, all including MECP2 gene. Mild to moderate cognitive impairment together with learning difficulties and speech delay were evident in each of our patients. Moreover, early inadequate behavioral patterns followed by persistent difficulties in the social and communication domains, as well as the occurrence of mild psychiatric disturbances, are common features of these three patients.
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    • "Because of advantageous skewing of X chromosome inactivation patterns in female carriers, MECP2 duplication syndrome primarily affects males (Ramocki, Tavyev, & Peters, 2010). More recent data suggest that MECP2 duplication syndrome accounts for approximately 1% of all cases of X-linked ID, but when males with ID who have other features of MECP2 duplication syndrome are also screened, the likelihood of identifying duplications involving the MECP2 locus approaches 15% (Friez et al., 2006; Lugtenberg et al., 2009). Prior studies have demonstrated considerable phenotypic variability among patients with MECP2 duplications for reasons that are not completely understood (Ramocki et al., 2010). "
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    ABSTRACT: Alterations in the X-linked gene MECP2 encoding the methyl-CpG-binding protein 2 have been linked to autism spectrum disorders (ASDs). Most recently, data suggest that overexpression of MECP2 may be related to ASD. To better characterize the relevance of MECP2 overexpression to ASD-related behaviors, we compared the core symptoms of ASD in MECP2 duplication syndrome to nonverbal mental age-matched boys with idiopathic ASD. Within the MECP2 duplication group, we further delineated aspects of the behavioral phenotype and also examined how duplication size and gene content corresponded to clinical severity. We compared ten males with MECP2 duplication syndrome (ages 3-10) with a chronological and mental age-matched sample of nine nonverbal males with idiopathic ASD. Our results indicate that boys with MECP2 duplication syndrome share the core behavioral features of ASD (e.g. social affect, restricted/repetitive behaviors). Direct comparisons of ASD profiles revealed that a majority of boys with MECP2 duplication syndrome are similar to idiopathic ASD; they have impairments in social affect (albeit to a lesser degree than idiopathic ASD) and similar severity in restricted/repetitive behaviors. Nonverbal mental age did not correlate with severity of social impairment or repetitive behaviors. Within the MECP2 duplication group, breakpoint size does not predict differences in clinical severity. In addition to social withdrawal and stereotyped behaviors, we also found that hyposensitivity to pain/temperature are part of the behavioral phenotype of MECP2 duplication syndrome. Our results illustrate that overexpression/increased dosage of MECP2 is related to core features of ASD. Autism Res 2012, ●●: ●●-●●. © 2012 International Society for Autism Research, Wiley Periodicals, Inc.
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    • "Triplication of the MECP2 locus may also occur and is associated with a similar, although more severe, phenotype (Del Gaudio et al., 2006). Genotype–phenotype correlation studies indicate that the minimal duplicated region that is necessary to cause the core phenotype involves MECP2 and the Inter- leukin-1 receptor-associated kinase 1 (IRAK1) genes (Del Gaudio et al., 2006; Lugtenberg et al., 2009). Transgenic mice engineered to overexpress the wild-type human MECP2 protein, at approximately twofold wild-type levels, developed a progressive disorder with seizures, reduced activity, repetitive movements, spasticity, and premature death (Collins et al., 2004). "
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    ABSTRACT: Rett syndrome is an X‐linked neurodevelopmental disorder that manifests in early childhood with developmental stagnation, and loss of spoken language and hand use, with the development of distinctive hand stereotypies, severe cognitive impairment, and autistic features. About 60% of patients have epilepsy. Seizure onset before the age of 3 years is unlikely, and onset after age 20 is rare. Diagnosis of Rett syndrome is based on key clinical elements that identify “typical” Rett syndrome but also “variant” or “atypical” forms. Diagnostic criteria have been modified only slightly over time, even after discovering that MECP2 gene alterations are present in >90% of patients with typical Rett syndrome but only in 50–70% of atypical cases. Over the last several years, intragenic or genomic alterations of the CDKL5 and FOXG1 genes have been associated with severe cognitive impairment, early onset epilepsy and, often, dyskinetic movement disorders, which have variably been defined as Rett variants. It is now clearly emerging that epilepsy has distinctive characteristics in typical Rett syndrome and in the different syndromes caused by CDKL5 and FOXG1 gene alterations. The progressive parting of CDKL5‐ and FOXG1‐gene–related encephalopathies from the core Rett syndrome is reflected by the effort to produce clearer diagnostic criteria for typical and atypical Rett syndrome. Efforts to characterize the molecular pathology underlying these developmental encephalopathies are pointing to abnormalities of telencephalic development, neuronal morphogenesis, maturation and maintenance, and dendritic arborization.
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