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.
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Acknowledgments
The authors thank the family members for their willingness to contribute to this research project. We are grateful to the excellent technical assistance of Karen Govaerts (KU Leuven, Belgium). This work was supported by grants from the VIB (Vlaams Instituut voor Biotechnologie), the Geconcerteerde Onderzoeks Acties (GOA) of the University of Leuven [grant number GOA/12/015 to GF], and from the Belgian Science Policy Office Interuniversity Attraction Poles (BELSPO-IAP) programme [grant number IAP P7/43-BeMGI to GF]. NF is a PhD fellow from the IWT (Agentschap voor Innovatie door Wetenschap en Technologie), Belgium. MB is a post-doctoral fellow and EDB is senior clinical investigator of the Fund for Scientific Research (FWO) Vlaanderen, Belgium.
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Fieremans, N., Bauters, M., Belet, S. et al. De novo MECP2 duplications in two females with intellectual disability and unfavorable complete skewed X-inactivation. Hum Genet 133, 1359–1367 (2014). https://doi.org/10.1007/s00439-014-1469-6
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DOI: https://doi.org/10.1007/s00439-014-1469-6