Xq28 duplications including MECP2 in five females: Expanding the phenotype to severe mental retardation

Center for Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
European journal of medical genetics (Impact Factor: 1.47). 03/2012; 55(6-7):404-13. DOI: 10.1016/j.ejmg.2012.02.009
Source: PubMed


Duplications leading to functional disomy of chromosome Xq28, including MECP2 as the critical dosage-sensitive gene, are associated with a distinct clinical phenotype in males, characterized by severe mental retardation, infantile hypotonia, progressive neurologic impairment, recurrent infections, bladder dysfunction, and absent speech.
Female patients with Xq duplications including MECP2 are rare. Only recently submicroscopic duplications of this region on Xq28 have been recognized in four females, and a triplication in a fifth, all in combination with random X-chromosome inactivation (XCI). Based on this small series, it was concluded that in females with MECP2 duplication and random XCI, the typical symptoms of affected boys are not present. We present clinical and molecular data on a series of five females with an Xq28 duplication including the MECP2 gene, both isolated and as the result of a translocation, and compare them with the previously reported cases of small duplications in females. The collected data indicate that the associated phenotype in females is distinct from males with similar duplications, but the clinical effects may be as severe as seen in males.

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    • "Another important parameter that can affect the clinical outcome is the integration site in the genome. If the duplicated region is inserted into an autosome (Bijlsma et al. 2012; Makrythanasis et al. 2010; Shimada et al. 2013a) or generated by inherited interchromosomal translocations (Auber et al. 2010; Bijlsma et al. 2012), the subsequent functional disomy always results in an increased MECP2 expression, thereby disturbing normal development. The clinical outcome might further be affected by the consequent disruption of genes. "
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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.
    Human Genetics 07/2014; 133(11). DOI:10.1007/s00439-014-1469-6 · 4.82 Impact Factor
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    • "In the only patient (case 3) with de novo Xq28 microduplication, the anomaly originated on the paternal X chromosome. Similarly, a paternal origin was demonstrated in other two females with de novo Xq28 interstitial duplications [32] in agreement with the X chromosome vulnerability at male meiosis [38]. "
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    ABSTRACT: Xq28 duplications, including MECP2 (methyl CpG-binding protein 2; OMIM 300005), have been identified in approximately 140 male patients presenting with hypotonia, severe developmental delay/intellectual disability, limited or absent speech and ambulation, and recurrent respiratory infections. Female patients with Xq28 duplication have been rarely reported and are usually asymptomatic. Altogether, only fifteen symptomatic females with Xq28 duplications including MECP2 have been reported so far: six of them had interstitial duplications while the remaining had a duplication due to an unbalanced X;autosome translocation. Some of these females present with unspecific mild to moderate intellectual disability whereas a more complex phenotype is reported for females with unbalanced X;autosome translocations. Here we report on the clinical features of three other adolescent to adult female patients with Xq28 interstitial duplications of variable size, all including MECP2 gene. Mild to moderate cognitive impairment together with learning difficulties and speech delay were evident in each of our patients. Moreover, early inadequate behavioral patterns followed by persistent difficulties in the social and communication domains, as well as the occurrence of mild psychiatric disturbances, are common features of these three patients.
    Molecular Cytogenetics 01/2014; 7(1):10. DOI:10.1186/1755-8166-7-10 · 2.14 Impact Factor
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    • "The majority of female MECP2 duplication carriers are unaffected due to a preferred inactivation of the aberrant X-chromosome. Random X inactivation was found to cause an associated phenotype in females that is distinct from those in males but can be as severe [13,14]. "
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    ABSTRACT: X-linked intellectual disability type Nascimento (MIM #300860), caused by mutations in UBE2A (MIM *312180), is characterized by craniofacial dysmorphism (synophrys, prominent supraorbital ridges, deep-set, almond-shaped eyes, depressed nasal bridge, prominent columella, hypoplastic alae nasi, and macrostomia), skin anomalies (hirsutism, myxedematous appearance, onychodystrophy), micropenis, moderate to severe intellectual disability (ID), motor delay, impaired/absent speech, and seizures. Hitherto only five familial point mutations and four different deletions including UBE2A have been reported in the literature. We present eight additional individuals from five families with UBE2A associated ID - three males from a consanguineous family, in whom we identified a small deletion of only 7.1 kb encompassing the first three exons of UBE2A, two related males with a UBE2A missense mutation in exon 4, a patient with a de novo nonsense mutation in exon 6, and two sporadic males with larger deletions including UBE2A. All affected male individuals share the typical clinical phenotype, all carrier females are unaffected and presented with a completely skewed X inactivation in blood. We conclude that 1.) X-linked intellectual disability type Nascimento is a clinically very distinct entity that might be underdiagnosed to date. 2.) So far, all females carrying a familial UBE2A aberration have a completely skewed X inactivation and are clinically unaffected. This should be taken in to account when counselling those families. 3.) The coverage of an array should be checked carefully prior to analysis since not all arrays have a sufficient resolution at specific loci, or alternative quantitative methods should be applied not to miss small deletions.
    Orphanet Journal of Rare Diseases 09/2013; 8(1):146. DOI:10.1186/1750-1172-8-146 · 3.36 Impact Factor
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