De novo MECP2 duplications in two females with intellectual disability and unfavorable complete skewed X-inactivation |
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Authors: | Nathalie Fieremans Marijke Bauters Stefanie Belet Jelle Verbeeck Anna C. Jansen Sara Seneca Filip Roelens Elfride De Baere Peter Marynen Guy Froyen |
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Affiliation: | 1. Human Genome Laboratory, VIB Center for the Biology of Disease, Leuven, Belgium 2. Human Genome Laboratory, Department of Human Genetics, KU Leuven, 3000, Leuven, Belgium 3. Department of Pediatric Neurology, Vrije Universiteit Brussel (VUB), UZ Brussel, Brussels, Belgium 4. Center for Medical Genetics, Vrije Universiteit Brussel (VUB), UZ Brussel, Brussels, Belgium 5. Department of Pediatric Neurology, AZ Delta, Roeselare, Belgium 6. Center for Medical Genetics, Ghent University, Ghent University Hospital, Ghent, Belgium
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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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