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Hum Genet. 2014 Nov;133(11):1359-67. doi: 10.1007/s00439-014-1469-6. Epub 2014 Jul 19.

De novo MECP2 duplications in two females with intellectual disability and unfavorable complete skewed X-inactivation.

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1
Human Genome Laboratory, VIB Center for the Biology of Disease, Leuven, Belgium.

Abstract

Xq28 microduplications of MECP2 are a prominent cause of a severe syndromic form of intellectual disability (ID) in males. Females are usually unaffected through near to complete X-inactivation of the aberrant X chromosome (skewing). In rare cases, affected females have been described due to random X-inactivation. Here, we report on two female patients carrying de novo MECP2 microduplications on their fully active X chromosomes. Both patients present with ID and additional clinical features. Mono-allelic expression confirmed complete skewing of X-inactivation. Consequently, significantly enhanced MECP2 mRNA levels were observed. We hypothesize that the cause for the complete skewing is due to a more harmful mutation on the other X chromosome, thereby forcing the MECP2 duplication to become active. However, we could not unequivocally identify such a second mutation by array-CGH or exome sequencing. Our data underline that, like in males, increased MECP2 dosage in females can contribute to ID too, which should be taken into account in diagnostics.

PMID:
25037250
DOI:
10.1007/s00439-014-1469-6
[Indexed for MEDLINE]

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