Pathogenic or not? Assessing the clinical relevance of copy number variants

Authors

  • JY Hehir-Kwa,

    Corresponding author
    1. Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands
    • Corresponding author: Jayne Hehir-Kwa, Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, PO Box 9101, 6500 HB, The Netherlands

      Tel.: +31 24 3613864

      fax: +31 24 36 68752

      e-mail: j.hehir@gen.umcn.nl

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  • R Pfundt,

    1. Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands
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  • JA Veltman,

    1. Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands
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  • N de Leeuw

    1. Department of Human Genetics, Nijmegen Centre for Molecular Life Sciences, Radboud University Medical Centre, Nijmegen, The Netherlands
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  • The authors have no conflict of interest to declare.

Abstract

The availability of commercially produced genomic microarrays has resulted in the wide spread implementation of genomic microarrays, often as a first-tier diagnostic test for copy number variant (CNV) screening of patients who are suspected for chromosomal aberrations. Patients with intellectual disability (ID) and/or multiple congenital anomalies (MCA) were traditionally the main focus for this microarray-based CNV screening, but the application of microarrays to other (neurodevelopmental) disorders and tumor diagnostics has also been explored and implemented. The diagnostic workflow for patients with ID is now well established, relying on the identification of rare CNVs and determining their inheritance patterns. However, experience gained through screening large numbers of samples has revealed many subtleties and complexities of CNV interpretation. This has resulted in a better understanding of the contribution of CNVs to genomic disorders not only via de novo occurrence, but also via X-linked and recessive inheritance models as well as through models taking into account mosaicisms, imprinting, and digenic inheritance. In this review, we discuss CNV interpretation within the context of these different genetic disease models and common pitfalls that can occur when searching for supportive evidence that a CNV is clinically relevant.

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