Wilson’s disease (WD) is an autosomal recessive disorder characterized by toxic accumulation of copper in the liver, brain, and other organs. The disease is caused by pathogenic variants in the ATP7B gene, which encodes a P-type copper transport ATPase. Diagnosing WD is associated with numerous difficulties due to the wide range of clinical manifestations and its unknown dependence on the physiological characteristics of the patient. This leads to a delay in the start of therapy and the subsequent deterioration of the patient’s condition. However, in recent years, molecular genetic testing of patients using next generation sequencing (NGS) has been gaining popularity. This immediately affected the detection speed of WD. If, previously, the frequency of this disease was estimated at 1:35,000–45,000 people, now, when conducting large molecular genetic studies, the frequency is calculated as 1:7026 people. This certainly points to the problem of identifying WD patients. This review provides an update on the performance of epidemiological studies of WD and describes normal physiological functions of the protein and diversified disfunctions depending on pathogenic variants of the ATP7B gene. Future prospects in the development of WD genetic diagnostics are also discussed.

Background/Objectives: Wilson’s disease (WD) (OMIM 277900) or hepatolenticular degeneration is an autosomal recessive disorder caused by impaired copper excretion with subsequent accumulation in the liver, brain, and other tissues of the body. The defects in copper metabolism are based on various pathogenic variants of the ATP7B gene encoding copper-transporting P-type ATPase. The aim of this work is to search for pathogenic variants of the ATP7B gene among Eastern Eurasian patient cohorts and to pick correlations between pathogenic variants, gender, age of onset of the disease, and the course of the disease. Methods: The material for the study was the biomaterial of 100 people. The search for mutations was carried out by Sanger sequencing. Multiple alignment of nucleotide sequences and their analysis was performed using the MEGA-X software. To study the genotype-phenotypic correlation, an analysis of the medical records of each patient was carried out. Results: Most common pathogenic variant (48%) in the sample is p.His1069Gln (c.3207C>A), located in exon 14 of the ATP7B gene. Pathogenic variants of p.Glu1064Lys (c.3190G>A)—20%—and p.Met769HisfsTer26 (c.2304insC)—8%—of exons 14 and 8 were also common. For patients with pathogenic alleles p.His1069Gln (c.3207C>A) and p.Glu1064Lys (c.3190G>A), typical deviations are mental and neurological manifestations of WD. In patients with the pathogenic allele p.Met769HisfsTer26 (c.2304insC), deviations are more characteristic of the liver and a combination of various symptoms that are atypical for WD. Conclusions: In this study, we were able to obtain differences in symptoms in patients with different pathogenic alleles of the ATP7B gene.

Background: Wilson’s disease (WD) is an autosomal recessive inherited disorder of copper metabolism resulting from various mutations in the ATP7B gene. Despite good knowledge and successful treatment options, WD is a severe disease that leads to disability, destructively affecting the quality of life of patients. Currently, none of the available laboratory tests can be considered universal and specific for the diagnosis of WD. Therefore, the introduction of genetic diagnostic methods that allow for the identification of the root cause at any stage over the course of the disease gave hope for an earlier solution of diagnostic issues in patients with WD. Methods: A method for the genetic diagnosis of WD based on ARMS PCR, DreamTaq Green PCR Master Mix and modified primers has been developed. This method is able to detect 14 mutant alleles: p.His1069Gln, p.Glu1064Lys, p.Met769HisfsTer26, p.Gly710Ser, p.Ser744Pro, p.Ala1135GlnfsTer13, p.Arg778Leu, p.Arg1041Trp, p.Arg616Gln, p.Arg778Gly, p.Trp779*, p.Val834Asp, p.Gly943Ser and p.3222_3243+21del43. Results: The primers for all mutations were highly specific with an absence of wild-type amplification. All the results were validated by direct DNA Sanger sequencing. Conclusions: This fast and economical method provides coverage for the identified common mutations, thereby making ARMS PCR analysis using DreamTaq Green PCR Master Mix and modified primers feasible and attractive for large-scale routine use.

Background: Wilson’s disease (WD, OMIM: 277900) is a rare autosomal recessive genetic disorder characterized by abnormal copper accumulation, manifesting as a variety of symptoms, including hepatocellular, neuropsychiatric, and mixed manifestations. Defects in copper metabolism are caused by various pathogenic variants of the ATP7B gene, which encodes the copper-transporting P-type ATPase. The aim of this study was to establish a correlation between various clinical outcomes and the localization of pathogenic variants in the structure of the ATP7B gene. Methods: A total of 139 unrelated patients with suspected Wilson’s disease from Primorsky Krai, Khabarovsk Krai, Kamchatka and Sakhalin were included. ATP7B pathogenic variants were screened using Sanger sequencing. Medical records of each patient were analyzed to investigate genotype–phenotype correlations. Molecular modeling of the protein folding was performed for the most frequent pathogenic variants. Results: The most common ATP7B pathogenic variants were p.His1069Gln (c.3207C>A) (0.23) and p.Glu1064Lys (c.3190G>A) (0.115) in exon 14, followed by p.Met769HisfsTer26 (c.2304insC) (0.072) in exon 8. An analysis of the clinical outcomes and structural modeling of the protein variants of ATP7B revealed that pathogenic variants localized in transmembrane domain 2 (TM2) lead to protein destabilization and cause more severe symptoms. Patients with pathogenic variants in TM2 are characterized by paroxysmal seizures, Kayser–Fleischer rings, liver changes on ultrasound examination, and other symptoms atypical for Wilson’s disease. Pathogenic variants localized in the N-domain of ATP7B cause less severe structural changes. These abnormalities have less severe consequences than those associated with pathogenic variants in TM2. Patients with pathogenic variants in the N-domain exhibited hyperkinesia, brain pathology, and severe impairment of mental, intellectual, and cognitive functions. Conclusions: This study demonstrates that the phenotypic manifestations of the disease may depend on the localization of the pathogenic variant.