Japanese Mental Retardation Consortium. 2012. Concomitant microduplications of MECP2 and ATRX in male patients with severe mental retardation

Department of Molecular Cytogenetics, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan.
Journal of Human Genetics (Impact Factor: 2.46). 12/2011; 57(1):73-7. DOI: 10.1038/jhg.2011.131
Source: PubMed


Investigations of chromosomal rearrangements in patients with mental retardation (MR) are particularly informative in the search for genes involved in MR. Here we report a family with concomitant duplications of methyl CpG binding protein 2 (MECP2) at Xq28 and ATRX (the causative gene for X-linked alpha thalassemia/mental retardation) at Xq21.1 detected by array-comparative genomic hybridization. The alterations were observed in a 25-year-old man who inherited them from his mother, who showed a normal phenotype and completely skewed X-chromosome inactivation, and also in his cousin, a 32-year-old man. The proband and his cousin showed severe MR, muscular hypotonia, recurrent respiratory infections and various other features characteristic of MECP2 duplication syndrome. However, the proband also had cerebellar atrophy never reported before in MECP2 duplication syndrome, suggesting that his phenotypes were modified through the ATRX duplication in an additive or epistatic manner.

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Available from: Eiji Nakagawa, Apr 23, 2014
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    • "Such mutations are commonly distinguished from low-level gains/losses using a direct threshold of array data. However, the threshold value often differs greatly, ranging from a log2 ratio of +/−0.4 for some studies [46,47] to as high as +/−1.0 for others [48,49]. The criteria we used to detect deletions were based on the aCGH patterns obtained from our mutant versus wild type hybridizations. "
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    ABSTRACT: Oligonucleotide microarray-based comparative genomic hybridization (CGH) offers an attractive possible route for the rapid and cost-effective genome-wide discovery of deletion mutations. CGH typically involves comparison of the hybridization intensities of genomic DNA samples with microarray chip representations of entire genomes, and has widespread potential application in experimental research and medical diagnostics. However, the power to detect small deletions is low. Here we use a graduated series of Arabidopsis thaliana genomic deletion mutations (of sizes ranging from 4 bp to ~5 kb) to optimize CGH-based genomic deletion detection. We show that the power to detect smaller deletions (4, 28 and 104 bp) depends upon oligonucleotide density (essentially the number of genome-representative oligonucleotides on the microarray chip), and determine the oligonucleotide spacings necessary to guarantee detection of deletions of specified size. Our findings will enhance a wide range of research and clinical applications, and in particular will aid in the discovery of genomic deletions in the absence of a priori knowledge of their existence.
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    • "Mutations as well as deletions of either one of those genes alone result in severe intellectual disability and autism, while no clinical impact of increased dosage of a unique gene other than MECP2 in the duplicated interval has been reported (Lugtenberg et al., 2009). It is possible the phenotypes in the probands are modified through an additive or epistatic effect between MECP2 and other genes within Xq28 duplication (Honda et al., 2012). Overall, the phenotype in our case manifested the hallmark of MECP2 duplication syndrome. "
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    ABSTRACT: Xq28 duplications encompassing the methyl CpG binding protein 2 (MECP2) in males exhibit a distinct phenotype, including developmental delay, facial dysmorphism, muscular hypotonia, intellectual disability, poor or absent speech, recurrent infections and early death. The vast majority of affected males inherit the MECP2 duplication from their usually asymptomatic carrier mothers. Only a few cases with Xq28 duplication originating from de novo unbalanced X/Y translocation have been reported and the paternal origin of the aberration has only been validated in three males in related to the literature. Here we present a karyotypically normal male with features characteristic of the MECP2 duplication syndrome. The genome-wide SNP genotyping shows a de novo 2.26-Mb duplication from Xq28 to the terminus. The genotypes of the SNPs within the duplicated region indicated a paternal origin. Furthermore, the results of fluorescence in situ hybridization (FISH) indicated a novel Xq:Yp translocation, characterized as der(Y)t(Y;X)(p11.32;q28), which suggests an aberrant occurred during spermatogenesis. The phenotype is compared to the previously reported cases with Xq28 duplication originated from an unbalanced X/Y translocation, and there was no specific part of the phenotype that could be contributed to the origin of parental imbalances. This report further highlights the capacity of high-molecular cytogenetic methods, such as SNP array and FISH, in the identification of submicroscopic rearrangement, structural configuration and parental origin of aberrant while in the evaluation of children with idiopathic developmental delay and intellectual disability.
    Full-text · Article · Oct 2013 · Gene
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    ABSTRACT: Journal of Human Genetics, official journal of the Japan Society of Human Genetics, publishes original articles and reviews on all aspects of human genetics, including medical genetics and genomics
    No preview · Article · Dec 2011 · Journal of Human Genetics
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