Journal Article

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

Morel, Hélène, Laplanche, Jean-Louis, Woimant, France, Collet, Corinne, Poujois, Aurélia, Page, Justine

2018

Overview

Background Wilson’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. Methods To 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. Results We 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. Conclusions This 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.

• Publisher: BioMed Central,BioMed Central Ltd,BMC
• Subject: Alleles / ATP7B / ATP7B gene / Biomedical and Life Sciences / Biomedicine / Brain - metabolism / Care and treatment / Ceruloplasmin / Chelating agents / Clinical prevalence / Cohort Studies / Copper / Copper - metabolism / Copper-transporting ATPases - genetics / Cytogenetics / Development and progression / Epidemiology / Excretion / France / Gene Function / Gene mutation / Genes / Genetic aspects / Genetic epidemiology and genetic associations / Genetic research / Genetics / Genomics / Health aspects / Hepatolenticular Degeneration - genetics / Heterozygote / Heterozygous carrier frequency / Human Genetics / Humans / Life Sciences / Liver / Liver - metabolism / Metabolic disorders / Methods / Mutation / Mutation - genetics / Next-generation sequencing / Phenotype / Phenotypes / Prevalence / Prevalence studies (Epidemiology) / Research Article / Santé publique et épidémiologie / Sequence Analysis, DNA - methods / Software / Wilson's disease