Identification of two inherited copy number variants in a male with autism supports two-hit and compound heterozygosity models of autism§

Authors

  • Susan Shur-Fen Gau M.D., Ph.D.,

    Corresponding author
    1. Department of Psychiatry, College of Medicine, National Taiwan University, Taipei, Taiwan
    2. Department of Psychiatry, National Taiwan University Hospital, Taipei, Taiwan
    3. Department of Psychology, Graduate Institute of Brain and Mind Sciences and Graduate Institute of Epidemiology and Preventive Medicine, National Taiwan University, Taipei, Taiwan
    • Department of Psychiatry, National Taiwan University Hospital and College of Medicine, No. 7, Chung-Shan South Road, Taipei 10002, Taiwan.
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  • Hsiao-Mei Liao,

    1. Institute of Biotechnology and Graduate Program of Biotechnology in Medicine, National Tsing Hua University, Hsinchu, Taiwan
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  • Chao-Chun Hong,

    1. Department of Psychiatry, College of Medicine, National Taiwan University, Taipei, Taiwan
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  • Wei-Hsien Chien,

    1. Department of Occupational Therapy, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
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  • Chia-Hsiang Chen

    Corresponding author
    1. Department of Psychiatry, College of Medicine, National Taiwan University, Taipei, Taiwan
    2. Division of Mental Health and Addiction Medicine, Institute of Population Health Sciences, National Health Research Institutes, Zhunan, Taiwan
    • Division of Mental Health and Addiction Medicine, Institute of Population Health Sciences, National Health Research Institutes, Zhunan 350, Taiwan.
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  • All the authors declare no conflicts of interest.

  • Hsiao-Mei Liao and Susan Shur-Fen Gau have equal contribution as the first author.

  • §

    How to cite this article: Gau SS-F, Liao H-M, Hong C-C, Chien W-H, Chen C-H. 2012. Identification of Two Inherited Copy Number Variants in a Male with Autism Supports Two-Hit and Compound Heterozygosity Models of Autism. Am J Med Genet Part B 159B:710–717.

Abstract

Autism is a childhood-onset neurodevelopmental disorder with complex genetic mechanism underlying its etiology. Recent studies revealed that a few single de novo copy number variants of genomic DNA (copy number variants [CNVs]) are pathogenic and causal in some sporadic cases, adding support to the hypothesis that some sporadic autism might be caused by single rare mutation with large clinical effect. In this study, we report the detection of two novel private CNVs simultaneously in a male patient with autism. These two CNVs include a microduplication of ∼4.5 Mb at chromosome 4q12-13.1 that was transmitted from his mother and a microdeletion of ∼1.8 Mb at 5q32 that was transmitted from his father. Several genes such as LPHN3, POU4F3, SH3RF2, and TCERG1 mapped to these two regions have psychiatric implications. However, the parents had only mild degree of attention deficit symptoms but did not demonstrate any obvious autistic symptoms or psychopathology. Our findings indicate that each of these two CNVs alone may not be pathogenic enough to cause clinical symptoms in their respective carriers, and hence they can be transmitted within each individual family. However, concomitant presence of these two CNVs might result in the clinical phenotypes of the affected patient reported here. Thus, our report of this family may represent an example to show that two hits of CNV and the presence of compound heterozygosity might be important mechanisms underlying the pathogenesis of autism. © 2012 Wiley Periodicals, Inc.

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