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: 1.49). 03/2012; 55(6-7):404-13. DOI: 10.1016/j.ejmg.2012.02.009
Source: PubMed

ABSTRACT 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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Available from: Maria-Isabel Tejada, Jan 01, 2014
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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 · 4.52 Impact Factor
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    • "Features of autism spectrum disorder (ASD), including repetitive behaviors, sensory processing difficulties , and difficulties with social affect are present in a large proportion of affected individuals (Peters et al. 2013; Ramocki et al. 2009). Females are less often affected, and the spectrum of phenotypes ranges from mild to the same severity as affected boys depending on the underlying genetic factors (Bijlsma et al. 2012; Grasshoff et al. 2011). Developmental regression, inclusive of a partial or complete loss of acquired highest spoken language skills (including babbling), and a loss of motor skills are major diagnostic criteria for classic Rett Syndrome (RTT) (Neul et al. 2010). "
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    ABSTRACT: The aim of this study was to determine the frequency, timing, and associated features of developmental regression in MECP2 duplication syndrome. We also examined whether duplication size was associated with regression. Comprehensive psychological evaluations were used to assess 17 boys with MECP2 duplication syndrome. Information about regression was gathered via parent report. Eight of 17 boys exhibited regression in language skills, while seven of 17 exhibited regression in other skill areas. Regression in "other skill" areas coincided with seizure onset and with a prior autism diagnosis in six of seven participants. Regression was not associated with duplication size. Questions remain as to why some boys regress, and future work is necessary to understand the underlying mechanism(s) that causes regression.
    Journal of Autism and Developmental Disorders 03/2013; DOI:10.1007/s10803-013-1796-9 · 3.06 Impact Factor
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    ABSTRACT: Background Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) located in the Xp22 region have been shown to cause a subset of atypical Rett syndrome with infantile spasms or early seizures starting in the first postnatal months. Methods We performed mutation screening of CDKL5 in 60 female patients who had been identified as negative for the methyl CpG-binding protein 2 gene (MECP2) mutations, but who had current or past epilepsy, regardless of the age of onset, type, and severity. All the exons in the CDKL5 gene and their neighbouring sequences were examined, and CDKL5 rearrangements were studied by multiplex ligation-dependent probe amplification (MLPA). Results Six previously unidentified DNA changes were detected, two of which were disease-causing mutations in the catalytic domain: a frameshift mutation (c.509_510insGT; p.Glu170GlyfsX36) and a complete deletion of exon 10. Both were found in patients with seizures that started in the first month of life. Conclusions This study demonstrated the importance of CDKL5 mutations as etiological factors in neurodevelopmental disorders, and indicated that a thorough analysis of the CDKL5 gene sequence and its rearrangements should be considered in females with Rett syndrome-like phenotypes, severe encephalopathy and epilepsy with onset before 5 months of age. This study also confirmed the usefulness of MLPA as a diagnostic screening method for use in clinical practice.
    BMC Medical Genetics 08/2012; 13(1):68. DOI:10.1186/1471-2350-13-68 · 2.45 Impact Factor
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