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Challenges in molecular diagnosis of Wilson disease
  1. Janice LV Reeve1,
  2. Ian M Frayling1,
  3. Patrick J Twomey1,2
  1. 1 Clinical Chemistry, St. Vincent’s University Hospital, Dublin, Ireland
  2. 2 School of Medicine, University College Dublin, Dublin, Ireland
  1. Correspondence to Dr Patrick J Twomey, Clinical Chemistry, St Vincent's University Hospital, Dublin, Ireland; taptwomey{at}

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A holistic approach is still required for the diagnosis of Wilson’s disease

The study by Poon et al 1 outlines the issues associated with the use of current molecular diagnostic methodologies to rule in or rule out a diagnosis of Wilson’s disease (WD) or primary copper excess.1 WD is an autosomal recessive condition caused by pathogenic variants in the ATP7B gene, which encodes P-type ATPase protein/enzyme. Loss-of-function of the protein prevents incorporation of copper into caeruloplasmin, with reduced biliary copper excretion and concomitant copper deposition in hepatic parenchymal cells, the brain, kidneys and cornea.2 Individual approaches to WD diagnosis have poor diagnostic accuracy. Clinical symptoms (e . g ., neurological decline) are ambiguous, clinical signs (e . g ., Kayser-Fleischer rings) take time to manifest, appropriate laboratory tests (i . e ., serum copper and caeruloplasmin, and urinary copper excretion) may be incomplete or inconclusive and genetic testing may miss rare variants. However, when these approaches are used synergistically for WD diagnosis, accuracy improves.

In this study, clinical information was available for 27 of the 51 patients who had WD genetic testing. Eight of these 27 patients had a clinical diagnosis of WD based on clinical presentation, Kayser-Fleischer rings and/or laboratory testing. In the remaining cases genetic testing was performed to exclude the condition. Of the eight patients with WD, three had no genetic diagnosis. Interpretation of genetic variation in the ATP7B gene and the clinical significance of variants identified is fraught with difficulty. It is well established that genetic variation does not always impact protein functionality. Interpretation of genetic variants necessitates the consistent use of guidelines …

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  • Handling editor Tahir S Pillay.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Patient consent for publication Not required.

  • Provenance and peer review Commissioned; internally peer reviewed.

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