Genetic studies discover novel coding and non-coding mutations in patients with Wilson's disease in China

Wilson disease (WD) is a rare autosomal recessive genetic disorder associated with various mutations in the ATP7B gene and leads to significant disability or death if untreated. Early diagnosis and proper therapy usually predict a good prognosis, especially in pre-symptomatic WD. Genetic testing provides an accurate and effective diagnostic method for the early diagnosis of WD.

We recruited 18 clinically diagnosed WD patients from 16 unrelated families and two independent individuals. The next-generation sequencing of the ATP7B gene was performed. The 293T cell lines were divided into wild-type (WT) ATP7B and mutated ATP7B groups. Cell proliferation was determined by Cell Counting Kit-8 (CCK-8) assay and apoptosis was detected by Annexin V/propidium iodide (PI) assays.

Pedigree analysis showed that compound heterozygous variants (17/18, 94.44%) were present in the majority of WD patients. A total of 33 ATP7B gene variants were identified, including three variants with uncertain significance (VUS) [two splice mutations (c.51+2T>G, c.1543+40G>A) and one frameshift mutation (c.3532_3535del)]. The CCK-8 and apoptosis assays demonstrated that the VUS of ATP7B could significantly affect the transportation of copper.

The study revealed genetic defects of 16 Chinese families and two independent individuals with WD, which enriched the mutation spectrum of the ATP7B gene worldwide and provided valuable information for studying the mutation types of ATP7B in the Chinese populations. Genetic testing in WD patients is necessary to shorten the time to initiate therapy, reduce damage to the liver and improve the prognosis.