Duplication of the MECP2 Region Is a Frequent Cause of Severe Mental Retardation and Progressive Neurological Symptoms in Males Hilde Van Esch, Marijke.

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Duplication of the MECP2 Region Is a Frequent Cause of Severe Mental Retardation and Progressive Neurological Symptoms in Males Hilde Van Esch, Marijke Bauters, Jaakko Ignatius, Mieke Jansen, Martine Raynaud, Karen Hollanders, Dorien Lugtenberg, Thierry Bienvenu, Lars Riff Jensen, Jozef Gécz, Claude Moraine, Peter Marynen, Jean-Pierre Fryns, Guy Froyen The American Journal of Human Genetics Volume 77, Issue 3, Pages 442-453 (September 2005) DOI: 10.1086/444549 Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigrees of the four families (L36, S49, T33, and T88) in which duplications at Xq28 have been identified. Blackened squares indicate affected males, and an asterisk (*) indicates the index patient of each family. Clinical pictures of index patients IV.1 (family L36) at age 1.5 years and III.2 (family S49) at age 12 years are shown. Data from X-inactivation studies are boxed and are shown below each female from whom we could obtain a DNA sample. The American Journal of Human Genetics 2005 77, 442-453DOI: (10.1086/444549) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 2 Identification of a duplication at Xq28 in family L36. A, X-chromosome array-CGH analysis of DNA (labeled with Cy5) from patient IV.1 mixed with DNA (labeled with Cy3) from a control male. Log2 normalized ratios are plotted against the position on the X chromosome (in Mb). Except for two polymorphic clones, the ratios for clones in unaffected genomic regions are within the normal interval (−0.36 to 0.36), whereas clones RP11-314B4 and RP11-119A22 at 153 Mb show ratios >0.60 (circled), which is indicative of a duplication. The “gap” at 60 Mb represents the centromeric region for which no clones were available. B, Schematic representation of the Xq28 region (152.20–153.20 Mb), showing the location of the qPCR primer sets, genomic clones, and genes present in this interval for which qPCR primers were designed. The duplicated region, based on the array-CGH and qPCR results, is shown below. C, qPCR data on DNA from the index patient of family L36 (unblackened bars), as well as from two controls (Co1 and Co2 [blackened bars and gray bars, respectively]). The values for the fold differences obtained for each primer set are given above the bars for the L36 patient only. The American Journal of Human Genetics 2005 77, 442-453DOI: (10.1086/444549) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 3 qPCR data obtained by use of the MECP2a primer set for DNA from two controls (Co1 and Co2 [blackened bars]) as well as 17 patients with XLMR (unblackened bars) who showed a phenotype similar to that presented by the index patient of family L36, who was used as a positive control (gray bar). The values for the fold differences in comparison with controls are given above the bars. A duplication was found in three additional patients from families S49 (patient 11), T33 (patient 16), and T88 (patient 17). The American Journal of Human Genetics 2005 77, 442-453DOI: (10.1086/444549) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 4 Schematic representation of the positions and sizes of the duplications at Xq28 in the four families with severe MR associated with spasticity. The locations of the qPCR primer sets, genomic clones, and genes present in this interval for which qPCR primers were designed are given. In the lower part, unblackened boxes represent normal regions, and blackened boxes are confirmed duplicated regions. The breakpoints of the duplications are located within the dotted lines. The duplication identified by Meins et al. (2005) is shown at the bottom, as is the common minimal duplicated region in all patients. The American Journal of Human Genetics 2005 77, 442-453DOI: (10.1086/444549) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure 5 Segregation of the duplication with the disease and increased MECP2 expression. A, Segregation was investigated by qPCR performed using the MECP2a primer set on all family members from whom we could obtain a DNA sample. The values for the fold differences in comparison with controls are given above the bars. A blackened bar indicates a male carrier (fold difference ∼2), and a gray bar indicates a female carrier (fold difference ∼1.5). B, Expression of MECP2 mRNA, by use of qPCR primers, in PBLs from the index patients of families L36, T33, and T88 (blackened bars), compared with controls (Co1–Co3 [unblackened bars]). The values for the fold differences in comparison with controls are given above the bars. The American Journal of Human Genetics 2005 77, 442-453DOI: (10.1086/444549) Copyright © 2005 The American Society of Human Genetics Terms and Conditions

Figure A1 The American Journal of Human Genetics 2005 77, 442-453DOI: (10.1086/444549) Copyright © 2005 The American Society of Human Genetics Terms and Conditions