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Unstable transmission of a familial complex chromosome rearrangement

Authors

  • Ellen van Binsbergen,

    Corresponding author
    1. Section of Genome Diagnostics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
    • Section of Genome Diagnostics, Deptartment of Medical Genetics, University Medical Center Utrecht, P.O. Box 85090, 3508 AB Utrecht, The Netherlands.
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  • Ron Hochstenbach,

    1. Section of Genome Diagnostics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
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  • Jacques Giltay,

    1. Section of Genome Diagnostics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
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  • Marielle Swinkels

    1. Section of Genome Diagnostics, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands
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  • How to Cite this Article: van Binsbergen E, Hochstenbach R, Giltay J, Swinkels M. 2012. Unstable transmission of a familial complex chromosome rearrangement. Am J Med Genet Part A 158A: 2888–2893.

Abstract

Complex chromosome rearrangements (CCRs) are rare genomic structural aberrations involving three or more breakpoints on two or more chromosomes. About one-third of all CCRs are familial. Transmittance of such a CCR results either in genomic imbalance due to abnormal segregation at meiosis I or is stably passed on to the next generation. Here we present a phenotypically normal mother with a CCR involving chromosomes 1, 3, and 5 that gave birth to a phenotypically abnormal son. The boy presented with hypotonia, mild facial dysmorphisms, and severe intellectual disability. Conventional karyotyping revealed the same apparently balanced CCR as in the mother. However, by use of array-comparative genome hybridization (array-CGH) and fluorescence in situ hybridization (FISH) we discovered that one of the derivative chromosomes in the patient contained a de novo rearrangement. It appears that during transmission of the CCR, an additional de novo deletion and duplication had arisen in one of the derivative chromosomes. We speculate that this was the result of the inverted duplication with a distal deletion mechanism. We also demonstrate the importance of high-resolution breakpoint analysis in CCRs and stress that genetic counseling of a familial CCR is not straightforward. To our knowledge, this would be the first description of this mechanism operating on a structurally abnormal chromosome. © 2012 Wiley Periodicals, Inc.

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