Tandem duplication of exons 1–7 neither impairs ATP7A expression nor causes a menkes disease phenotype

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.