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The Expanding Role of MBD Genes in Autism: Identification of a MECP2 Duplication and Novel Alterations in MBD5, MBD6, and SETDB1

Authors

  • Holly N. Cukier,

  • Joycelyn M. Lee,

  • Deqiong Ma,

  • Juan I. Young,

  • Vera Mayo,

  • Brittany L. Butler,

  • Sandhya S. Ramsook,

  • Joseph A. Rantus,

  • Alexander J. Abrams,

  • Patrice L. Whitehead,

  • Harry H. Wright,

  • Ruth K. Abramson,

  • Jonathan L. Haines,

  • Michael L. Cuccaro,

  • Margaret A. Pericak-Vance,

    Corresponding author
    • John P. Hussman Institute for Human Genomics, University of Miami, Miller School of Medicine, Miami, FL
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  • John R. Gilbert


Address for correspondence and reprints: Margaret A. Pericak-Vance, John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Professor of Human Genomics, 1501 NW 10th Avenue, BRB-314 (M860), University of Miami, Miller School of Medicine Miami, FL 33136. E-mail: mpericak@med.miami.edu; John R. Gilbert, Center for Genome Technology, John P. Hussman Institute for Human Genomics, Dr. John T. Macdonald Foundation Department of Human Genetics, 1501 NW 10th Avenue, BRB-510 (M860), University of Miami, Miller School of Medicine Miami, FL 33136. E-mail: jgilbert@med.miami.edu

Abstract

The methyl-CpG-binding domain (MBD) gene family was first linked to autism over a decade ago when Rett syndrome, which falls under the umbrella of autism spectrum disorders (ASDs), was revealed to be predominantly caused by MECP2 mutations. Since that time, MECP2 alterations have been recognized in idiopathic ASD patients by us and others. Individuals with deletions across the MBD5 gene also present with ASDs, impaired speech, intellectual difficulties, repetitive behaviors, and epilepsy. These findings suggest that further investigations of the MBD gene family may reveal additional associations related to autism. We now describe the first study evaluating individuals with ASD for rare variants in four autosomal MBD family members, MBD5, MBD6, SETDB1, and SETDB2, and expand our initial screening in the MECP2 gene. Each gene was sequenced over all coding exons and evaluated for copy number variations in 287 patients with ASD and an equal number of ethnically matched control individuals. We identified 186 alterations through sequencing, approximately half of which were novel (96 variants, 51.6%). We identified 17 ASD specific, nonsynonymous variants, four of which were concordant in multiplex families: MBD5 Tyr1269Cys, MBD6 Arg883Trp, MECP2 Thr240Ser, and SETDB1 Pro1067del. Furthermore, a complex duplication spanning of the MECP2 gene was identified in two brothers who presented with developmental delay and intellectual disability. From our studies, we provide the first examples of autistic patients carrying potentially detrimental alterations in MBD6 and SETDB1, thereby demonstrating that the MBD gene family potentially plays a significant role in rare and private genetic causes of autism. Autism Res 2012, 5: 385–397. © 2012 International Society for Autism Research, Wiley Periodicals, Inc.

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