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Background  Duplications of the X-linked  MECP2  gene are associated with moderate to severe intellectual disability, epilepsy, and neuropsychiatric illness in males, while triplications are associated with a more severe phenotype. Most carrier females show complete skewing of X-inactivation in peripheral blood and an apparent susceptibility to specific personality traits or neuropsychiatric symptoms.    Methods  We describe the clinical phenotype of a pedigree segregating a duplication of  MECP2  found on clinical array comparative genomic hybridization. The position, size, and extent of the duplication were delineated in peripheral blood samples from affected individuals using multiplex ligation-dependent probe amplification and fluorescence  in situ  hybridization, as well as targeted high-resolution oligonucleotide microarray analysis and long-range PCR. The molecular consequences of the rearrangement were studied in lymphoblast cell lines using quantitative real-time PCR, reverse transcriptase PCR, and western blot analysis.    Results  We observed a partial  MECP2  duplication in an adult male with epilepsy and mild neurocognitive impairment who was able to function independently; this phenotype has not previously been reported among males harboring gains in  MECP2  copy number. The same duplication was inherited by this individual’s daughter who was also affected with neurocognitive impairment and epilepsy and carried an additional copy-number variant. The duplicated segment involved all four exons of  MECP2 , but excluded almost the entire 3' untranslated region (UTR) ,  and the genomic rearrangement resulted in a  MECP2 - TEX28  fusion gene mRNA transcript. Increased expression of  MECP2  and the resulting fusion gene were both confirmed; however, western blot analysis of lysates from lymphoblast cells demonstrated increased MeCP2 protein without evidence of a stable fusion gene protein product.    Conclusion  The observations of a mildly affected adult male with a  MECP2  duplication and paternal transmission of this duplication are unique among reported cases with a duplication of  MECP2 . The clinical and molecular findings imply a minimal critical region for the full neurocognitive expression of the  MECP2  duplication syndrome, and suggest a role for the 3′ UTR in mitigating the severity of the disease phenotype.

A partial MECP2 duplication in a mildly affected adult male: a putative role for the 3' untranslated region in the MECP2 duplication phenotype