Extending the scope of diagnostic chromosome analysis: Detection of single gene defects using high-resolution SNP microarrays

Authors

  • Damien L. Bruno,

    1. VCGS Cytogenetics Laboratory, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia
    2. Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Australia
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  • Zornitza Stark,

    1. Genetic Health Services Victoria, VCGS, Royal Children's Hospital, Parkville, Australia
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  • David J. Amor,

    1. Genetic Health Services Victoria, VCGS, Royal Children's Hospital, Parkville, Australia
    2. Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Australia
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  • Trent Burgess,

    1. VCGS Cytogenetics Laboratory, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia
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  • Kathy Butler,

    1. VCGS Cytogenetics Laboratory, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia
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  • Sylvea Corrie,

    1. VCGS Cytogenetics Laboratory, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia
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  • David Francis,

    1. VCGS Cytogenetics Laboratory, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia
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  • Devika Ganesamoorthy,

    1. VCGS Cytogenetics Laboratory, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia
    2. Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Australia
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  • Louise Hills,

    1. VCGS Cytogenetics Laboratory, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia
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  • Paul A. James,

    1. Genetic Health Services Victoria, VCGS, Royal Children's Hospital, Parkville, Australia
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  • Darren O'Rielly,

    1. VCGS Cytogenetics Laboratory, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia
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  • Ralph Oertel,

    1. VCGS Cytogenetics Laboratory, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia
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  • Ravi Savarirayan,

    1. Genetic Health Services Victoria, VCGS, Royal Children's Hospital, Parkville, Australia
    2. Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Australia
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  • Krishnamurthy Prabhakara,

    1. VCGS Cytogenetics Laboratory, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia
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  • Nicholas Salce,

    1. VCGS Cytogenetics Laboratory, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia
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  • Howard R. Slater

    Corresponding author
    1. VCGS Cytogenetics Laboratory, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Australia
    2. Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Parkville, Australia
    • VCGS Pathology, Murdoch Children's Research Institute, Royal Children's Hospital, Parkville 3052, Australia
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  • Communicated by Barend Mas

Abstract

Microarray analysis has provided significant advances in the diagnosis of conditions resulting from submicroscopic chromosome abnormalities. It has been recommended that array testing should be a “first tier” test in the evaluation of individuals with intellectual disability, developmental delay, congenital anomalies, and autism. The availability of arrays with increasingly high probe coverage and resolution has increased the detection of decreasingly small copy number changes (CNCs) down to the intragenic or even exon level. Importantly, arrays that genotype SNPs also detect extended regions of homozygosity. We describe 14 examples of single gene disorders caused by intragenic changes from a consecutive set of 6,500 tests using high-resolution SNP microarrays. These cases illustrate the increased scope of cytogenetic testing beyond dominant chromosome rearrangements that typically contain many genes. Nine of the cases confirmed the clinical diagnosis, that is, followed a “phenotype to genotype” approach. Five were diagnosed by the laboratory analysis in the absence of a specific clinical diagnosis, that is, followed a “genotype to phenotype” approach. Two were clinically significant, incidental findings. The importance of astute clinical assessment and laboratory-clinician consultation is emphasized to optimize the value of microarrays in the diagnosis of disorders caused by single gene copy number and sequence mutations. 32:1500–1506, 2011. ©2011 Wiley Periodicals, Inc.

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