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.

Safety and status report of SARS-CoV-2 vaccination in patients with Wilson's disease.

“…Anhui where the research team is located is a clinical research center of the State Administration of Traditional Chinese Medicine of the People's Republic of China for major and di cult diseases -Wilson's disease. 30 WD patients in Anhui and its border areas are more convenient to seek medical treatment. Therefore, the number of patients in Anhui, Jiangsu, and Shandong is relatively high.…”

A retrospective cohort study: vaccination status and safety analysis of SARS-CoV-2 vaccine in patients with Wilson's disease

“…Anhui, where the research team is located at a clinical research center of the State Administration of Traditional Chinese Medicine of the People's Republic of China for major and di cult diseases -Wilson's disease. 38 WD patients in Anhui and its border areas are more convenient to seek medical treatment. Therefore, the numbers of patients in Anhui, Jiangsu, and Shandong were relatively high.…”

Role of serum ceruloplasmin in the diagnosis of Wilson's disease: A large Chinese study

“…According to previous sequencing results (12), 1,147 patients harbored two disease-causing variants (201 homozygotes and 946 compound heterozygotes). Moreover, 112 WD cases had only one variant with no second mutation detected, and 19 patients with no potential disease-causing variants were identified.…”

“…Dilution linearity was observed in the range of 0~0.800 g/L (with a regression coefficient of r 2 > 0.990). The exonic sequences and the intron–exon boundaries of ATP7B were amplified using a polymerase chain reaction, as previously described ( 12 ).…”