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Variant ATRX Syndrome with Dysfunction of ATRX and MAGT1 Genes

Authors

  • Ying Qiao,

    1. Department of Pathology, University of British Columbia (UBC), Vancouver, BC, Canada
    2. Department of Medical Genetics, UBC, Vancouver, BC, Canada
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    • These authors are considered as first coauthors.

  • Kajari Mondal,

    1. Department of Human Genetics, Emory University, Atlanta, Georgia
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    • These authors are considered as first coauthors.

  • Valentina Trapani,

    1. Istituto di Patologia Generale, Università Cattolica del Sacro Cuore, Rome, Italy
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    • These authors are considered as first coauthors.

  • Jiadi Wen,

    1. Department of Pathology, University of British Columbia (UBC), Vancouver, BC, Canada
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  • Gillian Carpenter,

    1. Human DNA Damage Response Disorders Group, Genome Damage & Stability Centre, University of Sussex, Sussex, UK
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  • Robert Wildin,

    1. St Lukes Hospital, Boise, Idaho, USA
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  • E. Magda Price,

    1. Department of Medical Genetics, UBC, Vancouver, BC, Canada
    2. Child and Family Research Institute, Vancouver, BC, Canada
    3. Department of Obstetrics and Gynaecology, UBC, Vancouver, BC, Canada
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  • Richard J. Gibbons,

    1. MRC Molecular Hematology Unit, John Radcliffe Hospital, Oxford, UK
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  • Jennifer Eichmeyer,

    1. St Lukes Hospital, Boise, Idaho, USA
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  • Ruby Jiang,

    1. Child and Family Research Institute, Vancouver, BC, Canada
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  • Barbara DuPont,

    1. Greenwood Genetic Center, Greenwood, South Carolina
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  • Sally Martell,

    1. Department of Pathology, University of British Columbia (UBC), Vancouver, BC, Canada
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  • Suzanne M. E. Lewis,

    1. Department of Medical Genetics, UBC, Vancouver, BC, Canada
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  • Wendy P. Robinson,

    1. Department of Medical Genetics, UBC, Vancouver, BC, Canada
    2. Child and Family Research Institute, Vancouver, BC, Canada
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  • Mark O'Driscoll,

    1. Human DNA Damage Response Disorders Group, Genome Damage & Stability Centre, University of Sussex, Sussex, UK
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  • Federica I. Wolf,

    Corresponding author
    1. Istituto di Patologia Generale, Università Cattolica del Sacro Cuore, Rome, Italy
    • Correspondence to: Evica Rajcan-Separovic, Department of Pathology (Cytogenetics), BC Child and Family Research Institute, University of British Columbia, 950 West 28th Avenue, Room 3060, Vancouver, BC V5Z 4H4, Canada. E-mail: eseparovic@cw.bc.ca; Michael E. Zwick, Department of Human Genetics, Whitehead Biomedical Research Building, 615 Michael St., Suite 301, Emory University, Atlanta, GA 30322. E-mail: mzwick@emory.edu; Federica I. Wolf, Istituto di Patologia Generale, Università Cattolica del Sacro Cuore, Facoltà di Medicina “A. Gemelli”, Largo F. Vito, 1, 00168 Rome, Italy. E-mail: federica.wolf@rm.unicatt.it

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  • Michael E. Zwick,

    Corresponding author
    1. Department of Human Genetics, Emory University, Atlanta, Georgia
    • Correspondence to: Evica Rajcan-Separovic, Department of Pathology (Cytogenetics), BC Child and Family Research Institute, University of British Columbia, 950 West 28th Avenue, Room 3060, Vancouver, BC V5Z 4H4, Canada. E-mail: eseparovic@cw.bc.ca; Michael E. Zwick, Department of Human Genetics, Whitehead Biomedical Research Building, 615 Michael St., Suite 301, Emory University, Atlanta, GA 30322. E-mail: mzwick@emory.edu; Federica I. Wolf, Istituto di Patologia Generale, Università Cattolica del Sacro Cuore, Facoltà di Medicina “A. Gemelli”, Largo F. Vito, 1, 00168 Rome, Italy. E-mail: federica.wolf@rm.unicatt.it

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  • Evica Rajcan-Separovic

    Corresponding author
    1. Department of Pathology, University of British Columbia (UBC), Vancouver, BC, Canada
    • Correspondence to: Evica Rajcan-Separovic, Department of Pathology (Cytogenetics), BC Child and Family Research Institute, University of British Columbia, 950 West 28th Avenue, Room 3060, Vancouver, BC V5Z 4H4, Canada. E-mail: eseparovic@cw.bc.ca; Michael E. Zwick, Department of Human Genetics, Whitehead Biomedical Research Building, 615 Michael St., Suite 301, Emory University, Atlanta, GA 30322. E-mail: mzwick@emory.edu; Federica I. Wolf, Istituto di Patologia Generale, Università Cattolica del Sacro Cuore, Facoltà di Medicina “A. Gemelli”, Largo F. Vito, 1, 00168 Rome, Italy. E-mail: federica.wolf@rm.unicatt.it

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  • Contract grant sponsors: The Canadian Institutes for Health Research (CIHR) (MOP 74502; PI); The Michael Smith Foundation for Health Research.

  • Communicated by Hamish S. Scott

ABSTRACT

A 0.8kb intronic duplication in MAGT1 and a single base pair deletion in the last exon of ATRX were identified using a chromosome X-specific microarray and exome sequencing in a family with five males demonstrating intellectual disability (ID) and unusual skin findings (e.g., generalized pruritus). MAGT1 is an Mg2+ transporter previously associated with primary immunodeficiency and ID, whereas mutations in ATRX cause ATRX-ID syndrome. In patient cells, the function of ATRX was demonstrated to be abnormal based on altered RNA/protein expression, hypomethylation of rDNA, and abnormal cytokinesis. Dysfunction of MAGT1 was reflected in reduced RNA/protein expression and Mg2+ influx. The mutation in ATRX most likely explains the ID, whereas MAGT1 disruption could be linked to abnormal skin findings, as normal magnesium homeostasis is necessary for skin health. This work supports observations that multiple mutations collectively contribute to the phenotypic variability of syndromic ID, and emphasizes the importance of correlating clinical phenotype with genomic and cell function analyses.

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