Genetic screening in Vietnamese patients suspected with Wilson disease

Abstract

Wilson disease (WD) is a rare autosomal recessive disorder of copper metabolism caused by pathogenic variants in the ATP7B gene. Patients with WD often suffer from delayed diagnosis due to complex clinical manifestations. When left untreated, patients develop neurological disabilities and life-threatening hepatic complications which resulted from copper accumulation. For WD, a diagnostic system was established according to integration of biochemical findings and molecular genetic testing for ATP7B causing variants. In Vietnam, comprehensive molecular studies integrating different genetic approaches for WD are still limited. This study aimed to identify disease-causing ATP7B variants in six unrelated Vietnamese patients clinically suspected of WD. Whole-exome sequencing (WES) was performed for all probands, with candidate variants confirmed by Sanger sequencing. For cases with only one or no pathogenic variant detected, multiplex ligation-dependent probe amplification (MLPA) was subsequently performed to find copy number variations (CNVs) in the ATP7B gene. WES revealed five ATP7B variants, including four rare variants classified as pathogenic or likely pathogenic: 2 missenses (c.3517G>A and c.2293G>A), 1 nonsense (c.314C>A), and 1 frameshift (c.2604delC). No CNVs of ATP7B were detected by MLPA in patients lacking biallelic mutations in this gene. Additionally, there were no candidate variants in genes related to differential diagnosis of Wilson disease. Our results expand the molecular spectrum of ATP7B variants and provide valuable insights for early molecular diagnosis, genetic counseling, and optimized management of WD in the Vietnamese population. For unresolved cases, it is important to explore the causing variants beyond the ATP7B coding sequence such as deep intronic variants and regulation regions.