WilsonGen a comprehensive clinically annotated genomic variant resource for Wilson’s Disease

Abstract

Wilson disease (WD) is one of the most prevalent genetic diseases with an estimated global carrier frequency of 1 in 90 and a prevalence of 1 in 30,000. The disease owes its genesis to Kinnier Wilson who described the disease, and is caused by accumulation of Copper (Cu) in various organs including the liver, central nervous system, cornea, kidney, joints and cardiac muscle which contribute to the characteristic clinical features of WD. A number of studies have reported genetic variants in the ATP7B gene from diverse ethnic and geographical origins. The recent advent of next-generation sequencing approaches has also enabled the discovery of a large number of novel variants in the gene associated with the disease. Previous attempts have been made to compile the knowledgebase and spectrum of genetic variants from across the multitude of publications, but have been limited by the utility due to the significant differences in approaches used to qualify pathogenicity of variants in each of the publications. The recent formulation of guidelines and algorithms for assessment of the pathogenicity of variants jointly put forward by the American College of Medical Genetics and the Association of Molecular Pathologists (ACMG &AMP) has provided a framework for evidence based and systematic assessment of pathogenicity of variants. In this paper, we describe a comprehensive resource of genetic variants in ATP7B gene manually curated from literature and data resources and systematically annotated using the ACMG & AMP guidelines for assessing pathogenicity. The resource therefore serves as a central point for clinicians and geneticists working on WD and to the best of our knowledge is the most comprehensive and only clinically annotated resource for WD. The resource is available at URL http://clingen.igib.res.in/WilsonGen/. We compiled a total of 3662 genetic variants from publications and databases associated with WD. Of these variants compiled, a total of 1458 were found to be unique entries. This is the largest WD database comprising 656 pathogenic/likely pathogenic variants reported classified according to ACMG & AMP guidelines. We also mapped all the pathogenic variants corresponding to ATP7B protein from literature and other databases. In addition, geographical origin and distribution of ATP7B pathogenic variants reported are also mapped in the database.

Copper Toxicity Is Not Just Oxidative Damage: Zinc Systems and Insight from Wilson Disease

“…Wilson Disease is the most well-documented disorder of Cu toxicity and is an autosomal recessive disorder of Cu metabolism with an estimated global allele frequency of 1:90 [ 45 ]. This rare disease is caused by a mutation in the ATP7B gene [ 46 ] that is characterized by excessive Cu accumulation, primarily in the liver, but also in other tissues including the brain [ 47 ].…”

Estimating the clinical prevalence of Wilson’s disease in the UK

“…Since the first identification of variants in the ATP7B gene being responsible for WD nearly 30 years ago (5)(6)(7), more than 500 variants have been linked to development of the disease (8,9). A more recent study reviewed a total of 1458 unique variants in the ATP7B gene identified from previous literature and data resources (10). They were annotated using American College of Medical Genetics and Genomics and the Association for Molecular Pathology criteria and a total of 656 pathogenic or likely pathogenic variants were curated into their database (10).…”

Investigation of the Wilson gene ATP7B transcriptional start site and the effect of core promoter alterations

“…rs762339422 (D2) displayed the most pronounced effect on expression. D2 has been observed in two Chinese Wilson disease patients without providing clear evidence for clinical relevance 36 and has been previously suggested to affect gene expression based on prediction 37 . However, since the expression repression was rather moderate, it is unlikely to be causative.…”