A partial MECP2 duplication in a mildly affected
adult male: a putative role for the 3'untranslated
region in the MECP2 duplication phenotype
Duplications of the X-linked MECP2 gene are associated with moderate to severe intellectualdisability, epilepsy, and neuropsychiatric illness in males, while triplications are associatedwith a more severe phenotype. Most carrier females show complete skewing of Xinactivationin peripheral blood and an apparent susceptibility to specific personality traits orneuropsychiatric symptoms.
We describe the clinical phenotype of a pedigree segregating a duplication of MECP2 foundon clinical array comparative genomic hybridization.
The position, size, and extent of theduplication were delineated in peripheral blood samples from affected individuals usingmultiplex ligation-dependent probe amplification and fluorescence in situ hybridization, aswell as targeted high-resolution oligonucleotide microarray analysis and long-range PCR.The molecular consequences of the rearrangement were studied in lymphoblast cell linesusing quantitative real-time PCR, reverse transcriptase PCR, and Western blot analysis.
We observed a partial MECP2 duplication in an adult male with epilepsy and mildneurocognitive impairment who was able to function independently; this phenotype has notpreviously been reported among males harboring gains in MECP2 copy number. The sameduplication was inherited by this individual's daughter who was also affected withneurocognitive impairment and epilepsy and carried an additional copy-number variant.
Theduplicated segment involved all four exons of MECP2, but excluded almost the entire 3'untranslated region (UTR), and the genomic rearrangement resulted in a MECP2-TEX28fusion gene mRNA transcript. Increased expression of MECP2 and the resulting fusion genewere both confirmed; however, Western blot analysis demonstrated increased MeCP2 proteinwithout evidence of a stable fusion gene protein product.
The observations of a mildly affected adult male with a MECP2 duplication and paternaltransmission of this duplication are unique among reported cases with a duplication ofMECP2.
The clinical and molecular findings imply a minimal critical region for the fullneurocognitive expression of the MECP2 duplication syndrome, and suggest a role for the 3'UTR in mitigating the severity of the disease phenotype.
Author: Neil A HanchardClaudia MB CarvalhoPatricia BaderAaron ThomeLisa Omo-GriffithDaniela del GaudioDavut PehlivanPing FangChristian P SchaafMelissa B RamockiJames R LupskiSau Wai Cheung Credits/Source: BMC Medical Genetics 2012, 13:71
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