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Microduplications in an autism multiplex family narrow the region of susceptibility for developmental disorders on 15q24 and implicate 7p21

Authors

  • Holly N. Cukier,

    1. John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida
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  • Daria Salyakina,

    1. John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida
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  • Sarah F. Blankstein,

    1. John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida
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  • Joycelyn L. Robinson,

    1. John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida
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  • Stephanie Sacharow,

    1. John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida
    2. Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, Florida
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  • Deqiong Ma,

    1. John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida
    2. Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, Florida
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  • Harry H. Wright,

    1. Department of Neuropsychiatry, University of South Carolina School of Medicine, Columbia, South Carolina
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  • Ruth K. Abramson,

    1. Department of Neuropsychiatry, University of South Carolina School of Medicine, Columbia, South Carolina
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  • Ramkumar Menon,

    1. Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia
    2. Department of Obstetrics and Gynecology, Rollins School of Public Health, Emory University, Atlanta, Georgia
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  • Scott M. Williams,

    1. Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee
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  • Jonathan L. Haines,

    1. Center for Human Genetics Research, Vanderbilt University, Nashville, Tennessee
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  • Michael L. Cuccaro,

    1. John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida
    2. Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, Florida
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  • John R. Gilbert,

    1. John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida
    2. Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, Florida
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  • Margaret A. Pericak-Vance Ph.D.

    Corresponding author
    1. John P. Hussman Institute for Human Genomics, Miller School of Medicine, University of Miami, Miami, Florida
    2. Dr. John T. Macdonald Foundation Department of Human Genetics, Miller School of Medicine, University of Miami, Miami, Florida
    • Associate Dean for Human Genomic Programs, Dr. John T. Macdonald Foundation Professor of Human Genomics, Director, John P. Hussman Institute for Human Genomics, 1501 NW 10th Avenue, BRB-314 (M860), University of Miami, Miller School of Medicine, Miami, FL 33136.
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  • Holly N. Cukier and Daria Salyakina contributed equally to this work.

  • How to Cite this Article: Cukier HN, Salyakina D, Blankstein SF, Robinson JL, Sacharow S, Ma D, Wright HH, Abramson RK, Menon R, Williams SM, Haines JL, Cuccaro ML, Gilbert JR, Pericak-Vance MA. 2011. Microduplications in an Autism Multiplex Family Narrow the Region of Susceptibility for Developmental Disorders on 15q24 and Implicate 7p21. Am J Med Genet Part B 156:493–501.

Abstract

Copy number variations (CNVs) play a crucial role in the intricate genetics of autism spectrum disorders. A region on chromosome 15q24 vulnerable to both deletions and duplications has been previously implicated in a range of phenotypes including autism, Asperger's syndrome, delayed development, and mild to severe mental retardation. Prior studies have delineated a minimal critical region of approximately 1.33 Mb. In this study, a multiplex autism family was evaluated for CNVs using genotyping data from the Illumina 1 M BeadChip and analyzed with the PennCNV algorithm. Variants were then identified that co-segregate with autism features in this family. Here, we report autistic first cousins who carry two microduplications concordant with disease. Both duplications were inherited maternally and found to be identical by descent. The first is an approximately 10,000 base pair microduplication within the minimal region on 15q24 that falls across a single gene, ubiquitin-like 7. This is the smallest duplication in the region to result in a neuropsychiatric disorder, potentially narrowing the critical region for susceptibility to developmental and autism spectrum disorders. The second is a novel, 352 kb tandem duplication on 7p21 that replicates part of the neurexophilin 1 and islet cell autoantigen 1 genes. The breakpoint junction falls within the intronic regions of these genes and demonstrates a microhomology of four base pairs. Each of these microduplications may contribute to the complex etiology of autism spectrum disorders. © 2011 Wiley-Liss, Inc.

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