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Detection of genomic copy number changes in patients with idiopathic mental retardation by high-resolution X-array-CGH: important role for increased gene dosage of XLMR genes

Authors

  • Guy Froyen,

    Corresponding author
    1. Human Genome Laboratory, Department for Molecular and Developmental Genetics, VIB, Leuven, Belgium
    2. Human Genome Laboratory, Department of Human Genetics, KU Leuven, Leuven, Belgium
    • Human Genome Laboratory, Dept. Human Genetics, VIB11, University of Leuven, Gasthuisberg, O&N1, Herestraat 49, PO Box 602, B-3000 Leuven, Belgium
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  • Hilde Van Esch,

    1. Department of Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium
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  • Marijke Bauters,

    1. Human Genome Laboratory, Department for Molecular and Developmental Genetics, VIB, Leuven, Belgium
    2. Human Genome Laboratory, Department of Human Genetics, KU Leuven, Leuven, Belgium
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  • Karen Hollanders,

    1. Human Genome Laboratory, Department for Molecular and Developmental Genetics, VIB, Leuven, Belgium
    2. Human Genome Laboratory, Department of Human Genetics, KU Leuven, Leuven, Belgium
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  • Suzanna G.M. Frints,

    1. Department of Clinical Genetics, University Hospital, Maastricht, The Netherlands
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  • Joris R. Vermeesch,

    1. Department of Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium
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  • Koen Devriendt,

    1. Department of Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium
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  • Jean-Pierre Fryns,

    1. Department of Human Genetics, University Hospital Gasthuisberg, Leuven, Belgium
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  • Peter Marynen

    1. Human Genome Laboratory, Department for Molecular and Developmental Genetics, VIB, Leuven, Belgium
    2. Human Genome Laboratory, Department of Human Genetics, KU Leuven, Leuven, Belgium
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  • Communicated by Arnold Munnich

Abstract

A tiling X-chromosome-specific genomic array with a theoretical resolution of 80 kb was developed to screen patients with idiopathic mental retardation (MR) for submicroscopic copy number differences. Four patients with aberrations previously detected at lower resolution were first analyzed. This facilitated delineation of the location and extent of the aberration at high resolution and subsequently, more precise genotype–phenotype analyses. A cohort of 108 patients was screened, 57 of which were suspected of X-linked mental retardation (XLMR), 26 were probands of brother pairs, and 25 were sporadic cases. A total of 15 copy number changes in 14 patients (13%) were detected, which included two deletions and 13 duplications ranging from 0.1 to 2.7 Mb. The aberrations are associated with the phenotype in five patients (4.6%), based on the following criteria: de novo aberration; involvement of a known or candidate X-linked nonsyndromic(syndromic) MR (MRX(S)) gene; segregation with the disease in the family; absence in control individuals; and skewed X-inactivation in carrier females. These include deletions that contain the MRX(S) genes CDKL5, OPHN1, and CASK, and duplications harboring CDKL5, NXF5, MECP2, and GDI1. In addition, seven imbalances were apparent novel polymorphic regions because they do not fulfill the proposed criteria. Taken together, our data strongly suggest that not only deletions but also duplications on the X chromosome contribute to the phenotype more often than expected, supporting the increased gene dosage mechanism for deregulation of normal cognitive development. Hum Mutat 28(10), 1034–1042, 2007. © 2007 Wiley-Liss, Inc.

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