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Challenges in molecular diagnosis of Wilson disease: viewpoint from the clinical laboratory
  1. Kok-Siong Poon1,
  2. Zhe Hao Teo2,
  3. Jun Hean Yap2,
  4. Evelyn SC Koay3,
  5. Karen Tan4
  1. 1 Molecular Diagnosis Centre, Department of Laboratory Medicine, National University Hospital, Singapore
  2. 2 Ngee Ann Polytechnic, Singapore
  3. 3 Department of Pathology, National University of Singapore, Singapore
  4. 4 Molecular Diagnosis Centre, Department of Laboratory Medicine, National University Hospitals, Singapore
  1. Correspondence to Dr Karen Tan, Laboratory Medicine, National University Hospital Singapore, Singapore 119704, Singapore; karen_ml_tan{at}

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Wilson disease

Wilson disease (WD), a disorder of copper metabolism resulting in copper accumulation in the liver and other organs, is an inherited autosomal recessive genetic condition.1 Diagnosis is challenging and is based on clinical symptoms (neuropsychiatric or hepatic dysfunction), clinical signs (presence of Kayser-Fleischer (KF) rings) and laboratory test results (abnormal liver function tests, low serum caeruloplasmin and elevated urinary copper excretion).2 However, the biochemical findings may be inconclusive as concentrations of serum caeruloplasmin and urinary copper in patients with WD can overlap with those of healthy individuals.2 To try to overcome such issues, laboratory-derived indices have been suggested, such as non-caeruloplasmin bound copper, percentage non-caeruloplasmin bound copper, copper caeruloplasmin ratio and copper adjusted for caeruloplasmin, but the reference ranges and cut-offs differ between laboratories.3–6 In addition, scoring systems exist,7 some of which may incorporate genetic testing.8 Molecular diagnostic testing is performed to confirm or exclude the diagnosis in patients with symptoms and biochemical findings suggestive of WD.2 7

Sequencing the ATP7B gene

Genetic testing of WD is performed by screening for loss-of-function variants in the ATP7B gene. Diagnostic confirmation can be achieved by identifying two pathogenic variants in the compound heterozygous state or a single pathogenic variant in the homozygous state. More than 500 WD-causing variants in the ATP7B gene including single nucleotide variants, small deletions and insertions have been reported in literature and public databases such as ClinVar, Leiden Open Variation Database, Human Genetic Variation Database and the Wilson Disease Mutation Database.9 Although the gene harbours several population-specific variants, many pathogenic variants throughout the entire gene have been found to be rare and only familial-specific.10 Therefore, screening tests that contain only specific, most frequent variants, although not as labour-intensive and time-consuming as whole gene screening, may miss rare pathogenic variants.

Sanger sequencing is currently …

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  • Handling editor Tahir S Pillay.

  • Contributors K-SP performed the laboratory tests and wrote the manuscript. ZHT and JHY performed the laboratory tests. ESCK advised on the study design and supervised the study and critically edited the manuscript. KT collected the clinical information and wrote the manuscript.

  • 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 Not commissioned; externally peer reviewed.

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