Article

Increased MECP2 gene copy number as the result of genomic duplication in neurodevelopmentally delayed males

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.
Genetics in Medicine (Impact Factor: 6.44). 01/2007; 8(12):784-92. DOI: 10.1097/01.gim.0000250502.28516.3c
Source: PubMed

ABSTRACT Mutations in the MECP2 gene are associated with Rett syndrome, an X-linked mental retardation disorder in females. Mutations also cause variable neurodevelopmental phenotypes in rare affected males. Recent clinical testing for MECP2 gene rearrangements revealed that entire MECP2 gene duplication occurs in some males manifesting a progressive neurodevelopmental syndrome.
Clinical testing through quantitative DNA methods and chromosomal microarray analysis in our laboratories identified seven male patients with increased MECP2 gene copy number.
Duplication of the entire MECP2 gene was found in six patients, and MECP2 triplication was found in one patient with the most severe phenotype. The Xq28 duplications observed in these males are unique and vary in size from approximately 200 kb to 2.2 Mb. Three of the mothers who were tested were asymptomatic duplication carriers with skewed X-inactivation. In silico analysis of the Xq28 flanking region showed numerous low-copy repeats with potential roles in recombination.
These collective data suggest that increased MECP2 gene copy number is mainly responsible for the neurodevelopmental phenotypes in these males. These findings underscore the allelic and phenotypic heterogeneity associated with the MECP2 gene and highlight the value of molecular analysis for patient diagnosis, family members at risk, and genetic counseling.

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    • "The striking finding that MECP2 nucleotide mutations or duplica- 71 tions cause Rett syndrome or MECP2 duplication syndrome, respective- 72 ly, suggests that careful regulation of this gene is necessary for correct 73 brain development and function, as both overexpression and reduced 74 expression are associated with neurodevelopmental disorders (Collins 75 et al., 2004; del Gaudio et al., 2006). Intriguingly, a loss of MECP2 "
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    • "Although the classical form of RTT is associated with loss-of-function MECP2 mutations, duplication of this gene is responsible for RTT-like neurological phenotypes (Del Gaudio et al., 2006); therefore, a fine-tuning of MeCP2 level might be important for normal development. "
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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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