Are the new genetic tools for diagnosis of Wilson disease helpful in clinical practice?

Espinós, Carmen; Ferenci, Péter

doi:10.1016/j.jhepr.2020.100114

Cited by 31 publications

(37 citation statements)

References 62 publications

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“…Stratified genetic analysis is recommended in order to achieve a reasonable diagnostic success rate with the aim to cover the whole ATP7B sequence and the different possible mutation types [ 70 , 71 ]. First, it is advisable to perform the study of the 21 coding exons and flanking intron sequences, since they harbor the majority (~95%) of the clinical variants ( Table 2 ).…”

Section: A Mendelian Disease Caused By Mutations In Atp7bmentioning

confidence: 99%

“…The vast majority are located in the coding and flanking intronic sequences throughout the entire gene, the most frequent being missense and nonsense mutations (>60%) (Table 2). Stratified genetic analysis is recommended in order to achieve a reasonable diagnostic success rate with the aim to cover the whole ATP7B sequence and the different possible mutation types [70,71]. First, it is advisable to perform the study of the 21 coding exons and flanking intron sequences, since they harbor the majority (~95%) of the clinical variants (Table 2).…”

Section: A Mendelian Disease Caused By Mutations In Atp7bmentioning

confidence: 99%

“…As mentioned before, diagnosis of WD is based on the Leipzig score and relies on imperfect clinical, biochemical, histological, and genetic findings. Despite technological advances, only one mutation or no mutation is identified in a relevant proportion of patients (~1-27%) [71]. Thus, Leung et al [84] estimated a clinical prevalence of 3.3 and a genetic prevalence of 14.3 per 100,000, disparities in part explained by the contribution of several factors such as epigenetics, metabolism, incomplete penetrance and missed diagnoses.…”

Section: Wilson's Disease Is Not That Rarementioning

confidence: 99%

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Wilson’s Disease: Facing the Challenge of Diagnosing a Rare Disease

et al. 2021

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Wilson disease (WD) is a rare disorder caused by mutations in ATP7B, which leads to the defective biliary excretion of copper. The subsequent gradual accumulation of copper in different organs produces an extremely variable clinical picture, which comprises hepatic, neurological psychiatric, ophthalmological, and other disturbances. WD has a specific treatment, so that early diagnosis is crucial to avoid disease progression and its devastating consequences. The clinical diagnosis is based on the Leipzig score, which considers clinical, histological, biochemical, and genetic data. However, even patients with an initial WD diagnosis based on a high Leipzig score may harbor other conditions that mimic the WD’s phenotype (Wilson-like). Many patients are diagnosed using current available methods, but others remain in an uncertain area because of bordering ceruloplasmin levels, inconclusive genetic findings and unclear phenotypes. Currently, the available biomarkers for WD are ceruloplasmin and copper in the liver or in 24 h urine, but they are not solid enough. Therefore, the characterization of biomarkers that allow us to anticipate the evolution of the disease and the monitoring of new drugs is essential to improve its diagnosis and prognosis.

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Section: A Mendelian Disease Caused By Mutations In Atp7bmentioning

confidence: 99%

Section: A Mendelian Disease Caused By Mutations In Atp7bmentioning

confidence: 99%

Section: Wilson's Disease Is Not That Rarementioning

confidence: 99%

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Wilson’s Disease: Facing the Challenge of Diagnosing a Rare Disease

et al. 2021

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“…As noted by the authors, this case underlines that genetic testing alone should not be used as the sole criterion for the diagnosis of WD, and that an appropriate combination of clinical history, clinical examination, and laboratory findings, including genetic testing if needed, remains necessary for the accurate diagnosis of WD. This very important point is one that has also been made and emphasised by others [10,11].…”

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confidence: 55%

Diagnosing Wilson’s Disease under the sword of Damocles

Pfeiffer

2020

Neurol Neurochir Pol.

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Introduction. Antos et al. [7] have reported a case of suspected uniparental disomy leading to an initial erroneous diagnosis of Wilson's Disease on the basis of genetic testing. They discuss the usefulness of the 64 Cu radioactive copper incorporation test as an often-overlooked diagnostic aid. Clinical reflections. Wilson's Disease is difficult to diagnose because of its rarity, diverse clinical presentations, and the absence of a single fail-safe diagnostic test. The identification of mutations in the ATP7B gene has been an invaluable aid in the diagnosis, but genetic testing alone is not infallible, and should not be used as the sole diagnostic test in arriving at a diagnosis of Wilson's Disease. Clinical implications. The diagnosis of Wilson's Disease must be based on a combination of findings that includes clinical history, clinical examination, and diagnostic testing. Genetic testing alone is insufficient.

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“…In Wilson disease patients carrying ATP7B mutations with incomplete inactivation of the gene product, the polymorphisms may confer a clinically relevant modification of the phenotype or disease penetrance. The majority of causative Wilson disease alterations confers such incomplete inactivation, these include (predominant location of occurrence is given in brackets): His1069Gln (Europe), Met769Val (UK), Arg969Gln (Greece), Met645Arg (Spain), Gly710Ser (Austria, Turkey) and Arg778Leu (Asia) 9 , 10 , 28 , 29 . We therefore investigated their impact more closely, first by assessing potential effects on transcriptional activity.…”

Section: Resultsmentioning

confidence: 99%

Investigation of the Wilson gene ATP7B transcriptional start site and the effect of core promoter alterations

Höflich

Brieger

Zeuzem

et al. 2021

Sci Rep

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Pathogenic genetic variants in the ATP7B gene cause Wilson disease, a recessive disorder of copper metabolism showing a significant variability in clinical phenotype. Promoter mutations have been rarely reported, and controversial data exist on the site of transcription initiation (the core promoter). We quantitatively investigated transcription initiation and found it to be located in immediate proximity of the translational start. The effects human single-nucleotide alterations of conserved bases in the core promoter on transcriptional activity were moderate, explaining why clearly pathogenic mutations within the core promoter have not been reported. Furthermore, the core promoter contains two frequent polymorphisms (rs148013251 and rs2277448) that could contribute to phenotypical variability in Wilson disease patients with incompletely inactivating mutations. However, neither polymorphism significantly modulated ATP7B expression in vitro, nor were copper household parameters in healthy probands affected. In summary, the investigations allowed to determine the biologically relevant site of ATP7B transcription initiation and demonstrated that genetic variations in this site, although being the focus of transcriptional activity, do not contribute significantly to Wilson disease pathogenesis.

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Are the new genetic tools for diagnosis of Wilson disease helpful in clinical practice?

Cited by 31 publications

References 62 publications

Wilson’s Disease: Facing the Challenge of Diagnosing a Rare Disease

Wilson’s Disease: Facing the Challenge of Diagnosing a Rare Disease

Diagnosing Wilson’s Disease under the sword of Damocles

Investigation of the Wilson gene ATP7B transcriptional start site and the effect of core promoter alterations

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