1. De novo MECP2 duplications in two females with intellectual disability and unfavorable complete skewed X-inactivation
- Author
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Guy Froyen, Anna Jansen, Filip Roelens, Jelle Verbeeck, Marijke Bauters, Peter Marynen, Sara Seneca, Stefanie Belet, Elfride De Baere, Nathalie Fieremans, Public Health Sciences, Medical Genetics, Mental Health and Wellbeing research group, Neurogenetics, Department of Embryology and Genetics, Reproduction and Genetics, and Clinical sciences
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Adolescent ,Methyl-CpG-Binding Protein 2 ,Biology ,Polymorphism, Single Nucleotide ,MECP2 ,X Chromosome Inactivation ,Gene Duplication ,Intellectual Disability ,Intellectual disability ,Gene duplication ,medicine ,Humans ,Exome ,genetics ,Child ,Skewed X-inactivation ,Genetics (clinical) ,X chromosome ,Exome sequencing ,In Situ Hybridization, Fluorescence ,Oligonucleotide Array Sequence Analysis ,Genetics ,Comparative Genomic Hybridization ,Gene Expression Profiling ,Sequence Analysis, DNA ,medicine.disease ,Human genetics ,Xq28 ,Pedigree ,nervous system diseases ,Gene Expression Regulation ,Mental Retardation, X-Linked ,Female ,Intelectual Disability ,Microsatellite Repeats - 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.
- Published
- 2014