Evidence for replicative mechanism in a CHD7 rearrangement in a patient with CHARGE syndrome

Authors

  • Matteo Vatta,

    Corresponding author
    1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
    2. Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, Indiana
    3. Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, Indiana
    • Correspondence to:

      Matteo Vatta, Ph.D., Department of Medical and Molecular Genetics, Indiana University School of Medicine, 975 Walnut Street, Indianapolis, IN 46202.

      E-mail: mvatta@iu.edu

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  • Zhiyv Niu,

    1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
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  • James R. Lupski,

    1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
    2. Department of Pediatrics, Baylor College of Medicine, Houston, Texas
    3. Texas Children's Hospital, Houston, Texas
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  • Philip Putnam,

    1. Division of Gastroenterology, Hepatology and Nutrition, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
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  • Katherine G. Spoonamore,

    1. Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis, Indiana
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  • Ping Fang,

    1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
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  • Christine M. Eng,

    1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
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  • Alecia S. Willis

    1. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas
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  • Disclosure Statement: M.V., Z.N., P.F., C.M.E., and A.S.W. at the time of performing the project were at the Medical Genetics Laboratories, a Diagnostic Laboratory at Baylor College of Medicine. J.R.L. is a paid consultant for Athena Diagnostics, has stock ownership in 23andMe and Ion Torrent Systems, and is a co-inventor on multiple United States and European patents related to molecular diagnostics for inherited neuropathies, eye diseases, and bacterial genomic fingerprinting. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from the chromosomal microarray analysis (CMA) and clinical exome sequencing offered in the Medical Genetics Laboratory (MGL; http://www.bcm.edu/geneticlabs/). To the best of our knowledge there are no other conflicts of interest to disclose and all procedures have been compliant with ethical regulations.

Abstract

Haploinsufficiency of CHD7 (OMIM# 608892) is known to cause CHARGE syndrome (OMIM# 214800). Molecular testing supports a definitive diagnosis in approximately 65–70% of cases. Most CHD7 mutations arise de novo, and no mutations affecting exon-7 have been reported to date. We report on an 8-year-old girl diagnosed with CHARGE syndrome that was referred to our laboratory for comprehensive CHD7 gene screening. Genomic DNA from the subject with a suspected diagnosis of CHARGE was isolated from peripheral blood lymphocytes and comprehensive Sanger sequencing, along with deletion/duplication analysis of the CHD7 gene using multiplex ligation-dependent probe amplification (MLPA), was performed. MLPA analysis identified a reduced single probe signal for exon-7 of the CHD7 gene consistent with potential heterozygous deletion. Long-range PCR breakpoint analysis identified a complex genomic rearrangement (CGR) leading to the deletion of exon-7 and breakpoints consistent with a replicative mechanism such as fork stalling and template switching (FoSTeS) or microhomology-mediated break-induced replication (MMBIR). Taken together this represents the first evidence for a CHD7 intragenic CGR in a patient with CHARGE syndrome leading to what appears to be also the first report of a mutation specifically disrupting exon-7. Although likely rare, CGR may represent an overlooked mechanism in subjects with CHARGE syndrome that can be missed by current sequencing and dosage assays. © 2013 Wiley Periodicals, Inc.

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