title: De novo MECP2 duplications in two females with intellectual disability and unfavorable complete skewed X-inactivation.
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.
authors.affiliation: Human Genome Laboratory, VIB Center for the Biology of Disease, Leuven, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Fieremans
authors.forename: Marijke
authors.initials: M
authors.lastname: Bauters
authors.forename: Stefanie
authors.initials: S
authors.lastname: Belet
authors.forename: Jelle
authors.initials: J
authors.lastname: Verbeeck
authors.forename: Anna C
authors.initials: AC
authors.lastname: Jansen
authors.forename: Sara
authors.initials: S
authors.lastname: Seneca
authors.forename: Filip
authors.initials: F
authors.lastname: Roelens
authors.forename: Elfride
authors.initials: E
authors.lastname: De Baere
authors.forename: Peter
authors.initials: P
authors.lastname: Marynen
authors.forename: Guy
authors.initials: G
authors.lastname: Froyen
mesh_terms: D000293:Adolescent; D002648:Child; D055028:Comparative Genomic Hybridization; D059472:Exome / Q000235:genetics; D005260:Female; D020440:Gene Duplication; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008607:Intellectual Disability / Q000235:genetics; D038901:X-Linked Intellectual Disability / Q000235:genetics*; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics*; D018895:Microsatellite Repeats / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017422:Sequence Analysis, DNA; D049951:X Chromosome Inactivation / Q000235:genetics*
chemical_list: C497392:MECP2 protein, human; D051783:Methyl-CpG-Binding Protein 2