Abstract
ATP7A duplications are estimated to represent the molecular cause of Menkes disease in 4–10% of affected patients. We identified a novel duplication of ATP7A exons 1–7 discovered in the context of a challenging prenatal diagnostic situation. All other reported ATP7A duplications (n = 24) involved intragenic tandem duplications, predicted to disrupt the normal translational reading frame and produce nonfunctional ATP7A proteins. In contrast, the exon 1–7 duplication occurred at the 5′ end of the ATP7A gene rather than within the gene and did not correspond to any known copy number variants. We hypothesized that, if the exon 1–7 duplication was in tandem, functional ATP7A molecules could be generated depending on promoter selection, mRNA splicing, and the proximal and distal duplication breakpoints and that Menkes disease would be averted. Here, we present detailed molecular characterization of this novel duplication, as well as 2-year postnatal clinical and biochemical correlations. The case highlights the ongoing need for cautious interpretation of prenatal genetic test results.
Competing interests: None declared
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We thank the patient’s parents for their kind cooperation in these studies.
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Communicated by: Gregory Enns
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All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from the parents of the patients included in the study.
This article does not contain any studies with animal subjects performed by the any of the authors.
Eun-Young Choi, Keyur Patel, Marie Reine Haddad, and Ling Yi performed the molecular and cell biological experiments described in this article. Courtney Holmes and David S. Goldstein performed the neurochemical analyses. Amalia Dutra and Evgenia Pak performed fluorescence in situ hybridization (FISH) experiments. Eun-Young Choi and Stephen Kaler planned the studies and wrote the manuscript.
All authors (Eun-Young Choi, Keyur Patel, Marie Reine Haddad, Ling Yi, Courtney Holmes, David S. Goldstein, Amalia Dutra, Evgenia Pak, and Stephen Kaler) declare that they have no conflict of interest.
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Choi, EY. et al. (2014). Tandem Duplication of Exons 1–7 Neither Impairs ATP7A Expression Nor Causes a Menkes Disease Phenotype. In: Zschocke, J., Baumgartner, M., Morava, E., Patterson, M., Rahman, S., Peters, V. (eds) JIMD Reports, Volume 20. JIMD Reports, vol 20. Springer, Berlin, Heidelberg. https://doi.org/10.1007/8904_2014_391
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DOI: https://doi.org/10.1007/8904_2014_391
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