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.

Keywords: ATP7B; Chinese; Genotype–phenotype correlation; Large cohort study; Wilson’s disease.

Fig. 1

Flowchart of study participants

Fig. 2

Characterization of genetic variants in the ATP7B gene. a Novel variants were visualized in relation to the ATP7B protein regions. b Various mutants identified in this study and their proportions. c Allele frequency of common ATP7B variants in Chinese patients. d Family distributions of patients in this study and allele frequencies of common variants in different regions of China

Fig. 3

Associations of sex (male), age-at-onset, and ATP7B variants with WD manifestations. a Binary logistic regression analysis of factors associated with neurologic presentation in hepatic and neurologic presentation patients (n = 941). b Binary logistic regression analysis of factors associated with acute hepatic WD in hepatic presentation patients (n = 276). c Binary logistic regression analysis of factors associated with dystonia, gait abnormality, swallowing difficulty, dysarthria, tremor, or salivation in neurologic presentation patients (n = 665). Only factors with significant associations in univariate analyses were included in the multivariate analysis. The P-values were adjusted with the Benjamini–Hochberg method. Cont., continuous variable, PTV, protein-truncating variants (e.g., frameshift, nonsense, splice sites)

Fig. 4

Effect of common ATP7B genotypes on symptom onset age of WD. a Allele frequencies of target variants according to age at onset. b Effects of genotype on age-at-onset in patients with hepatic presentation. c Effects of genotype on age-at-onset in patients with neurologic presentation. Data were evaluated by one-way analysis of variance followed by Scheffe multiple comparison test. PTV, protein-truncated variants (e.g., frameshift, nonsense, splice sites)