Twenty-four novel mutations in Wilson disease patients of predominantly European ancestry

Cox, Diane W.; Prat, Lisa M.; Walshe, J. M.; Heathcote, Jenny; Gaffney, Dairena

doi:10.1002/humu.9358

Cited by 35 publications

(21 citation statements)

References 13 publications

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“…52524268C > Trs191312027111c.2605G > Ap.Gly869ArgP-Type ATPASeAsian: 0.023%6.10DDC3411pathogenic[16]g.52520559G > Ars201061621113c.2921C > Tp.Thr974MetP-Type ATPaseAfrican: 0.033%5.94DDC28.810pathogenic11g.52513198 T > Crs200911496117c.3688A > Gp.Ile1230ValP-Type ATPaseAsian: 0.012%4.89DDC24.911pathogenic11g.52511409 T > Crs5659705311Intron 19c.4021 + 3A > G donor splicing site utilisation: − 100%p. ?–Asian: 0.2791%1.17–DC9.70710pathogenic[19]g.52509155G > Ars181250704421c.4135C > Tp.Pro1379Ser–European: 0.18%2.87DDC28.540pathogenic[15]g.52518403-52518403delinsG–114c.3083-3085delinsGp.Lys1028Serfs*40P-Type ATPase–4.97 1.34 4.89DDC–11pathogenicthis studyg.52524498C > Grs181388674110c.2485G > Cp.Asp829HisP-Type ATPase–6.10DDC3210Likely pathogenicthis studyg.52511803 T > C–118c.3712A > Gp.Lys1238GluP-Type ATPase–4.81DDC27.510Likely pathogenicthis studyg.52511700G > C–<...>…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2018

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BackgroundWilson’s disease (WD) is a rare autosomal recessive metabolic disease caused by ATP7B gene mutations tat cause excessively high copper levels, particularly in the liver and brain. The WD phenotype varies in terms of its clinical presentation and intensity. Diagnosing this metabolic disorder is important as a lifelong treatment, based on the use of copper chelating agents or zinc salts, is more effective if it’s started early. Worldwide prevalence of WD is variable, with an average of 1/30,000. In France, a recent study based on French health insurance data estimated the clinical prevalence of the disease to be around 3/200,000.MethodsTo estimate the genetic prevalence of WD in France, we analysed the ATP7B gene by Next Generation Sequencing from a large French cohort of indiscriminate subjects.ResultsWe observed a high heterozygous carrier frequency of ATP7B in France. Among the 697 subjects studied, 18 variants classified as pathogenic or probably pathogenic were found at heterozygous level in 22 subjects (22 alleles/1394 alleles), yielding a prevalence of 0.032 or 1/31 subjects.ConclusionsThis considerable and unexplained discrepancy between the heterozygous carrier frequency and the clinical prevalence of WD may be explained by the clinical variability, the incomplete penetrance and the existence of modifiers genes. It suggests that the molecular analysis of ATP7B should be interpreted with caution, always alongside copper assays (ceruloplasmin, relative exchangeable copper, 24 h-urinary copper excretion) with particular respect to exome sequencing.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2018

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“…Her first mutation, proline992leucine, has been reported in East Asian populations [13,14] with an estimated frequency of 1.7% among disease genes [15]. The second mutation is alanine861threonine [11]. Her Leipzig score was 6, and also rose to 10 taking into account the mutated ATP7B genes.…”

Section: Case Descriptionsmentioning

confidence: 96%

“…After results from mutation analysis became available, her score was 10 (WD considered highly likely for score P4). One of her mutations, threonine766methionine, is a missense mutation described in British and East Asian populations [11,12]. Her other mutation, IVS16 + 1 g fi a, is a splice mutation, reported in British populations [12].…”

Section: Case Descriptionsmentioning

confidence: 99%

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Three atypical cases of Wilson disease: Assessment of the Leipzig scoring system in making a diagnosis

Xuan¹,

Bookman²,

Cox³

et al. 2007

Journal of Hepatology

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“…For mutation analysis, PCR amplification of the 21 exons and flanking regions of the ATP7B gene was performed using intronic primer pairs and the PCR conditions previously described [22]. Bi-directional sequencing was performed on AB 3730 Genetic Analyser with dye-termination chemistry, using SeqScape software.…”

Section: Methodsmentioning

confidence: 99%

Screening of Wilson’s disease in a psychiatric population: difficulties and pitfalls. A preliminary study

et al. 2017

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BackgroundWilson’s disease (WD) is a rare autosomal-recessive, inherited disorder caused by a mutation in the copper-transporting gene ATP7B affecting the liver and nervous system. About 30% of patients with WD may initially present with psychiatric symptoms, and diagnosis can be difficult to establish. The objectives of the present preliminary study were [1] to evaluate the relevance of serum copper (Cu) and ceruloplasmin (Cp) measures in hospitalized patients with psychiatric disorders; and [2] to identify possible mutations in the ATP7B gene in patients with abnormal biological copper profile.MethodsAll psychiatric patients who participated in this study were hospitalized in Saint-Jean de Dieu Hospital (Lyon, France). Cp was measured by immunoturbidimetry and serum Cu by inductively coupled plasma-optical emission spectrometry. When Cp and serum Cu levels were inferior to, respectively, 0.18 g/L and 0.88 mg/L in combination with atypical psychiatric presentations, complete clinical examinations were performed by multidisciplinary physicians specialized in WD. In addition, mutation detection in the ATP7B gene was performed.ResultsA total of 269 patients completed the study. (1) 51 cases (19%) showed both decreased Cp and Cu concentrations. (2) Molecular genetic tests were performed in 29 patients, and one ATP7B mutation (heterozygous state) was found in four patients. We identified three different missense mutations: p.His1069Gln, c.3207C>A (exon 14), p.Pro1379Ser, c.4135C>T (exon 21) and p.Thr1434Met, c.4301C>T (exon 21). No pathogenic mutation on either ATP7B allele was detected.ConclusionResults of Cp and/or serum Cu concentrations below the normal limits are common in patients with psychiatric disorders and nonrelevant and/or informative for the WD diagnosis. WD diagnosis is based on a combination of clinical and biological arguments. Psychiatric patients with suspicion of WD should be evaluated in a reference center. Trial registration CPP Lyon Sud-Est IVNo 10/044, CNIL No DR-2011-470, Afssaps No B100832-40 and CCTIRS No 10.612 bis, registered 8 June 2010

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Twenty-four novel mutations in Wilson disease patients of predominantly European ancestry

Cited by 35 publications

References 13 publications

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

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

Three atypical cases of Wilson disease: Assessment of the Leipzig scoring system in making a diagnosis

Screening of Wilson’s disease in a psychiatric population: difficulties and pitfalls. A preliminary study

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