Dataset Information

Clinical and genetic characterization of a large cohort of patients with Wilson's disease in China.

ABSTRACT:

Background

Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism caused by ATP7B (encoding a copper-transporting P-type ATPase) variants that shows various characteristics according to race and geographical region. This study was aimed to provide a comprehensive analysis of ATP7B variants in China and to investigate a plausible role of common variants in WD manifestations.

Methods

A total of 1366 patients (1302 index patients and 64 siblings) clinically diagnosed with WD (Leipzig score ≥ 4) were recruited. They underwent ATP7B gene sequencing and information of age and symptoms at onset was collected. The genotype-phenotype correlation was assessed in the index patients who were examined with two pathogenic variants and onset with hepatic (n = 276) or neurologic (n = 665) symptoms.

Results

We identified 294 potentially pathogenic ATP7B variants (112 truncating, 174 missense, 8 in-frame) in the 1302 index patients, including 116 novel variants. The most frequent variant was c.2333G>T (R778L, allele frequency: 28.96%), followed by c.2975C>T (P992L, 13.82%), c.2621C>T (A874V, 5.99%), c.2755C>G (R919G, 2.46%), and c.3646G>A (V1216M, 1.92%). In 1167 patients, both pathogentic variants were identified, of which 532 different variant combinations were found. By binary logistic regression analysis, the factor associated with neurological presentation was high age-at-onset, but not sex, protein-truncating variant (PTV), or the common missense variants (R778L, P992L, and A874V). In the neurological group, low age-at-onset was a factor associated with dystonia, gait abnormality, and salivation; high age-at-onset was a factor associated with tremor; and the sex, low age-at-onset and A874V were independent factors associated with dysarthria. In addition, PTV, R778L, and P992L were predominant in early-onset patients, whereas A874V was predominant in late-onset patients, and patients with R778L/A874V genotype displayed a higher age-at-onset than patients with R778L/R778L or R778L/P992L genotype.

Conclusions

Our work expanded the ATP7B variant spectrum and highlighted the differences among patients with WD in age-at-onset and ATP7B variants, which may provide some valuable insights into the diagnosis, counseling, and treatment of patients with WD.

SUBMITTER: Zhang S

PROVIDER: S-EPMC8883683 | biostudies-literature | 2022 Feb

REPOSITORIES: biostudies-literature

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Publications

Clinical and genetic characterization of a large cohort of patients with Wilson's disease in China.

Zhang Shijie S Yang Wenming W Li Xiang X Pei Pei P Dong Ting T Yang Yue Y Zhang Jing J

Translational neurodegeneration 20220228 1

<h4>Background</h4>Wilson's disease (WD) is an autosomal recessive disorder of copper metabolism caused by ATP7B (encoding a copper-transporting P-type ATPase) variants that shows various characteristics according to race and geographical region. This study was aimed to provide a comprehensive analysis of ATP7B variants in China and to investigate a plausible role of common variants in WD manifestations.<h4>Methods</h4>A total of 1366 patients (1302 index patients and 64 siblings) clinically dia ...[more]

PMID: 35220961

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Project description:Background: Wilson's disease (WD) is an autosomal recessive disease that is caused by mutations in the ATP7B (a copper-transporting P-type ATPase) gene. The disease has a low prevalence and is characterized by a copper metabolism disorder. However, various characteristics of the disease are determined by race and geographic region. We aimed to discover novel ATP7B mutations in pediatric patients with WD from Yunnan province, where there is a high proportion of ethnic minorities. We also performed a comprehensive analysis of ATP7B mutations in the different ethnic groups found in Southwest China. Methods: We recruited 45 patients who had been clinically diagnosed with WD, from 44 unrelated families. Routine clinical examinations and laboratory evaluations were performed and details of age, gender, ethnic group and symptoms at onset were collected. Direct sequencing of the ATP7B gene was performed in 39 of the 45 patients and their families. Results: In this study, participants came from seven different ethnic groups in China: Han, Bai, Dai, Zhuang, Yi, Hui and Jingpo. Three out of ten patients from ethnic minorities presented with elevated transaminases, when compared to the majority of the Han patients. Forty distinct mutations (28 missense, six splicing, three non-sense, two frameshift and one mutation of uncertain significance) were identified in the 39 patients with WD. Four of the mutations were novel and the most frequent mutation was c.2333G > T (p.R778L, allelic frequency: 15.38%). Using the phenotype-genotype correlation analysis, patients from ethnic minorities were shown to be more likely to have homozygous mutations (p = 0.035) than Han patients. The patients who carried the c.2310C > G mutation had lower serum ceruloplasmin levels (p = 0.012). In patients with heterozygous mutations, c.3809A > G was significantly associated with ethnic minorities (p = 0.042). The frequency of a protein-truncating variant (PTV) in Han patients was 34.38% (11/32), while we did not find PTV in patients from ethnic minorities. Conclusion: This study revealed genetic defects in 39 pediatric patients with WD from Yunnan province. Four novel mutations were identified and have enriched the WD database. We characterized the genotypes and phenotypes in different minorities, which will enhance the current knowledge on the population genetics of WD in China.

Project description:Objectives: None of the previous studies have focused on the genetic effect on neurological worsening in neurological Wilson's disease (WD) patients following chelator therapy. We aimed to evaluate the clinical and genetic role in the occurrence of neurological worsening. Methods: We retrospectively reviewed the medical records of neurological WD patients who received initial chelator therapy and genetic test. Clinical, laboratory, and genetic data were collected. The genotype was classified into two types: 1) severe mutation genotype: patients who carried at least one of the following three types of mutations: frameshift mutation, splicing mutation, or nonsense mutation; 2) non-severe mutation genotype: patients who only carried missense mutations. Then, the clinical features and genotype of the patients with and without neurological worsening were investigated. Results: Forty-seven neurological WD patients were identified with a median age at onset of 16.17 years (range 7.75-47 years) and 35 (74.5%) males. The mean interval from onset to diagnosis was 0.6 years (range: 0.5 months-6.25 years). Neurological deterioration was observed in 29 patients (61.7%) and the other 18 patients (38.3%) were stable or improved during anti-copper treatment. The neurological worsening was completely irreversible in 6 cases (20.7%) and partially irreversible in 16 cases (55.2%). The common deteriorated symptoms were as follows: rigidity in 20 cases (69%), speech difficulties in 20 cases (69%)), walking difficulties in 13 cases (44.8%), dysphagia in 9 cases (31%), and salivation in 9 cases (31%). The patients with neurological worsening had significantly younger age (p = 0.028), shorter delayed diagnosis time (p = 0.011), higher rate of dystonia (p = 0.003), and severe mutation genotype (p = 0.036), compared to those without neurological worsening. Conclusion: We found that younger age of onset, the presence of dystonia, and genotype with severe mutations may be predictive of neurological worsening in the neurological WD patients that received chelator therapy. For those patients, chelator therapy should be given with caution and needs closer observation during follow-up.

Dataset Information

Clinical and genetic characterization of a large cohort of patients with Wilson's disease in China.

Background

Methods

Results

Conclusions

Publications

Clinical and genetic characterization of a large cohort of patients with Wilson's disease in China.

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