High genetic carrier frequency of Wilson’s disease in France: discrepancies with clinical prevalence

Collet, Corinne; Laplanche, Jean‐Louis; Page, Justine; Morel, Hélène; Poujois, Aurélia

doi:10.1186/s12881-018-0660-3

Cited by 51 publications

(50 citation statements)

References 22 publications

(24 reference statements)

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“…The larger studies clearly suggest that there are still a number of undiagnosed cases. This is supported by prevalence differences among geographical areas and age groups in the French study, the sex differences in the Taiwan study, and the increase of prevalence estimates with time in the Hong Kong study . Another factor affecting clinical prevalence is potential masking as other diseases, e.g., nonalcoholic steatohepatitis or dementia.…”

Section: Discussionmentioning

confidence: 85%

“…In a recent French study, ATP7B DNA was sequenced in 697 patients with diseases other than hepatic and neurologic and without a family history of WD. Among the 1,394 alleles examined, they identified 15 alleles that have been classified as pathogenic, 7 “likely pathogenic” alleles, and 15 alleles with “variants of uncertain significance.” The “likely pathogenic” variants had never been identified in patients with WD, but computer analysis predicted them to be deleterious for protein function.…”

Section: Resultsmentioning

confidence: 99%

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The Prevalence of Wilson’s Disease: An Update

et al. 2020

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Background and Aims In 1984, Scheinberg and Sternlieb estimated the prevalence of Wilson’s disease to be 1:30,000 based on the limited available data. This suggested a large number of overlooked cases with potentially fatal consequences. The “Scheinberg‐Sternlieb Estimate” is still widely used, although more recent clinical and genetic studies of higher quality are now available. In the present study, we included these data to update the prevalence estimate. Approach and Results A MEDLINE Ovid, Science Citation Index Expanded, and PubMed systematic search for all relevant studies on the prevalence of Wilson’s disease was conducted. In total, 59 studies (50 clinical and 9 population‐based genetic) were included in the final analysis. We identified 4 recent clinical studies based on nationwide databases of high quality, providing prevalence estimates from 1:29,000 to 1:40,000. Higher frequency populations do exist because of frequent first‐cousin marriages and/or a higher mutation frequency. When calculating prevalence from the incidence related to number of births, estimates were 1:40,000‐1:50,000. Clinical screening studies, including examination for Kayser‐Fleischer rings or ceruloplasmin, did not improve these estimates because of insufficient sample size or selection biases. Population‐based genetic studies in US and UK populations were not in disagreement with the clinically based estimates. At the same time, studies from France and Sardinia suggested that the genetic prevalence may be 3‐4 times higher than the clinical disease prevalence. This raises the question whether the penetrance is indeed 100% as generally assumed. Conclusions The original prevalence estimate from 1984 of 1:30,000‐1:50,000 still appears valid, at least for the United States, Europe, and Asia. In some population‐based studies, the genetic prevalence was 3‐4 times higher than clinically based estimates. The question of penetrance needs further evaluation.

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Section: Discussionmentioning

confidence: 85%

Section: Resultsmentioning

confidence: 99%

The Prevalence of Wilson’s Disease: An Update

et al. 2020

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“…7 Reports on the prevalence of WD are inconsistent depending on the region of the world and the methods used to diagnose or screen for WD. 10 Furthermore, another study 11 in France showed a high heterozygous carrier frequency of ATP7B yielding a prevalence of 1:31 subjects. By sequencing the entire coding region and adjacent splice sites of ATP7B in 1000 control subjects in the UK, the frequency of carriers with two pathogenic ATP7B mutations was estimated to be of 1 in 7026.…”

Section: Introductionmentioning

confidence: 98%

“…By sequencing the entire coding region and adjacent splice sites of ATP7B in 1000 control subjects in the UK, the frequency of carriers with two pathogenic ATP7B mutations was estimated to be of 1 in 7026. 10 Furthermore, another study 11 in France showed a high heterozygous carrier frequency of ATP7B yielding a prevalence of 1:31 subjects. The authors explained this discrepancy partly due to the clinical variability of WD with incomplete penetrance and existence of modifier genes.…”

Section: Introductionmentioning

confidence: 98%

The dilemma to diagnose Wilson disease by genetic testing alone

Stättermayer

Entenmann

Gschwantler

et al. 2019

Eur J Clin Investigation

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Background Wilson disease (WD) is an autosomal recessive disorder of hepatic copper excretion. About sixty per cent of patients present with liver disease. WD is considered a fatal disease if undiagnosed and/or untreated but recent data indicate that disease penetrance may not be 100%. Materials and Methods All patients underwent liver biopsy as part of the diagnostic workup. Genetic testing for ATP7B was performed by Sanger sequencing. Results We report on a large family with multiple affected siblings. The first patient (male, 31 years) underwent orthotopic liver transplantation (OLT) because of fulminant WD. He was homozygous for p.G710A. One asymptomatic brother (37 years) had the same mutation. He is doing well on chelation therapy. Fifteen years later, a second‐degree sibling (female, 16 years) presented with fulminant WD and underwent OLT. She was compound heterozygote (p.G710A/p.G710S). Further family screening revealed a third mutation (p.V536A) in a female (21 years) and male (16 years) compound‐heterozygote sibling (p.G710A/p.V536A). In both, serum ceruloplasmin and 24‐hour urinary copper excretion were normal. Liver biopsy showed normal histology and a quantitative hepatic copper content within the normal range or only slightly elevated (19 and 75 μg/g dry weight, respectively). No decoppering treatment was initiated so far. Conclusion Genetic testing alone is not always sufficient to diagnose WD in asymptomatic patients, and human mutation databases should be used with caution. Even patients carrying two disease‐causing mutations do not necessarily have demonstrable alteration of copper metabolism. Asymptomatic siblings diagnosed by genetic screening require further testing before initiating treatment.

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“…25 Prevalence approaches 1:30,000 in some countries where diagnostic awareness of WD is high, such as Austria 26 and France 27 . However, recent population-genetic studies based on the computer analysis of observed variants have led to estimates of WD prevalence of 1:1,400 28 , 1:7,100 29 or 1:6,500 30 . If true, these studies suggest that at least 75% of people affected by the disease are undiagnosed with potentially fatal consequences.…”

Section: Introductionmentioning

confidence: 99%

Benchmarking Computational Methods for Estimating the Pathogenicity of Wilson’s Disease Mutations

Tang

Sandahl

Ott

et al. 2019

Preprint

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Genetic variations in the gene encoding the copper-transport protein ATP7B are the primary cause of Wilson's disease. Controversially, clinical prevalence seems much smaller than prevalence estimated by genetic screening tools, causing fear that many people are undiagnosed although early diagnosis and treatment is essential. To address this issue, we benchmarked 16 state-of-the-art computational disease-prediction methods against established data of missense ATP7B mutations.Our results show that the quality of the methods vary widely. We show the importance of optimizing the threshold of the methods used to distinguish pathogenic from non-pathogenic mutations against data of clinically confirmed pathogenic and non-pathogenic mutations. We find that most methods use thresholds that predict too many ATP7B mutations to be pathogenic. Thus, our findings explain the current controversy on Wilson's disease prevalence, because meta analysis and text search methods include many computational estimates that lead to higher disease prevalence than clinically observed. Since proteins differ widely, a one-size-fits-all threshold for all proteins cannot distinguish efficiently pathogenic and non-pathogenic mutations, as shown here. We also show that amino acid changes with small evolutionary substitution probability, mainly due to amino acid volume, are more associated with disease, implying a pathological effect on the conformational state of the protein, which could affect copper transport or ATP recognition and hydrolysis. These findings may be a first step towards a more quantitative genotype-phenotype relationship of Wilson's disease.

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High genetic carrier frequency of Wilson’s disease in France: discrepancies with clinical prevalence

Cited by 51 publications

References 22 publications

The Prevalence of Wilson’s Disease: An Update

The Prevalence of Wilson’s Disease: An Update

The dilemma to diagnose Wilson disease by genetic testing alone

Benchmarking Computational Methods for Estimating the Pathogenicity of Wilson’s Disease Mutations

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