Interrelationship between clinical phenotype and genotype in patients with Wilson's disease. Summary of the doctoral thesis in medical sciences. 321.01 – Internal diseases (gastroenterology and hepatology).

Abstract

Current status and importance of the problem addressed. Wilson's disease (WD), also known as lenticular degeneration, is an autosomal recessive pathology caused by mutations in the ATP7B gene, located on chromosome 13 (gene locus: 13q 14.3–921.1) [1]. Dysfunction of the ATP7B protein results in impaired biliary excretion of copper (Cu) and, consequently, in the accumulation of Cu in the liver and extrahepatic tissues. The clinical picture is very varied, with hepatic and neurological involvement being the main forms of presentation. The disease can become symptomatic at any age or may remain asymptomatic for an indefinite period. [2] Over 900 pathogenic variants of this gene have been identified, and efforts to associate them with disease phenotypes have been inconclusive and controversial [3]. The difficulty in establishing genotype-phenotype correlation can be attributed to several factors: the large number of mutations that occur in only a few families and the clinical heterogeneity of WD patients, even among members of the same family. The fact that most patients are compound heterozygotes, having different mutations on each allele, makes it difficult to correlate a phenotype with a mutant allele [4]. In addition, occupational exposure to Cu has been shown to cause genome-wide changes and DNA damage [5]. This aspect, in combination with epigenetic modulators and environmental factors, may play a role in the phenotypic heterogeneity of WD patients. These barriers can be partially overcome by studying the genetics of WD in homozygous patients. [6] A multifamily study in an isolated population with a high degree of genetic and environmental homogeneity from a mountainous region of Romania revealed an equal influence of putative genetic modifiers and environmental factors on the clinical presentation and age at onset of WD in patients with a given genotype [7]. Specific mutations in the ATP7B gene are more common in populations with consanguineous marriages. For example, in Lebanon, consanguinity has a prevalence of 35.5%, increasing the likelihood of homozygosity for autosomal recessive diseases. [8] Chabik and coauthors have highlighted the presence of a similar clinical and biochemical manifestation of WD with a high intra-familial concordance, suggesting that analogous factors shared in the same families may strongly influence the presentation of the disease [4]. On the other hand, some authors have shown significant differences in phenotype despite the same genotype, suggesting a significant influence on the WD phenotype by epigenetic/environmental factors [9, 10]. A study from China has demonstrated a relationship between some pathogenetic variants, different clinical forms, and the occurrence of WD. For example, the p.Arg919Gly mutation was associated with neurological disease, and p.Arg778Leu was associated with a younger age of onset and lower serum ceruloplasmin (Cp) and Cu levels. However, the study only included the Chinese population, so further studies are needed in Caucasian patients with WD. [11] Furthermore, the incidence of this disease in certain regions seems to be closely related to the so-called “founder effect,” indicating the property of certain “isolated” communities to contract autosomal recessive genetic diseases more frequently, because mutations that are normally rare are found much more frequently in these communities [12]. However, recent research has established that the heterogeneity of clinical phenotypes does not only depend on the degree of functional alteration of ATP7B or genetic mutation but also on pathogenic mutations in other genes involved in Cu homeostasis, defined in the same studies as “copper homeostasis genes” or CHGs [13], which could be analyzed in the future. Future research may change the therapeutic approach of WD patients about their genotype, suggesting the need for combination therapy in case the most severe pathogenic mutations, associated with ATP7B and/or CHG polymorphisms, are present. Currently, a complex approach is required in WD management, analyzing the genotype-phenotype correlation in the light of identifying diagnostic/screening, treatment, and prognosis possibilities. Research hypothesis. As a result of this research for the first time in the Republic of Moldova, we will be able to identify a genetic profile of the patient with WD, which will allow the identification of mutations involved in the development of the disease on the territory of the country, as well as the inherited status (homozygous recessive, compound heterozygous, simple heterozygous and without mutations detected at the level of the ATP7B gene). Belonging to a clinical phenotype will allow the determination of the predominant clinical presentation as well as factors that could influence the clinical evolution of the disease. Highlighting associations between phenotype and genotype would highlight new solutions in the diagnosis and treatment of the patient with WD. Familial evaluation of the proband would identify new family members in an asymptomatic clinical stage, which would allow the initiation of early therapy with the prevention of complications and irreversible lesions. The purpose of the scientific research is to study and establish the correlation between the clinical phenotype and genotype of the patient with Wilson's disease in order to develop an algorithm for diagnosis and family screening of patients with Wilson's disease. The purpose of scientific research is to study and establish the correlation between the clinical phenotype and the genotype of the patient with Wilson's disease in order to develop an algorithm for diagnosis and family screening of patients with Wilson's disease. To achieve the goal, the following general research objectives were proposed: 1. Identifying demographic aspects in patients with Wilson's disease in the Republic of Moldova; 2. Defining clinical phenotypes determined in patients with Wilson's disease; 3. Characterization of the spectrum of genetic mutations in patients with Wilson's disease; 4. Assessing clinical-genetic interrelationships in patients with Wilson's disease; 5. Studying the impact of family screening in patients with Wilson's disease; 6. Developing a diagnostic and familial screening algorithm for patients with Wilson's disease [...].