Abstracts of the 2023 Annual Meeting of the ALEH
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Introduction and ObjectivesWilson's disease (WD) is a rare genetic disease presenting more than 900 mutations in the ATP7B gene. The knowledge of the regional distribution of these mutations can improve the diagnosis of WD. We aimed to evaluate the frequency of ATP7B mutations in a WD Brazilian cohort and the association with disease phenotypes.
Patients / Materials and MethodsWe performed molecular analysis by NGS of the 21 exons of ATP7B (Mendelics Genomic Analysis Laboratory) in patients with diagnosis of WD and in first-degree relatives undergoing WD investigation, followed in a single hepatology center. Demographic data and predominant type of WD presentation were assessed.
Results and Discussion28 patients were included (60% female; mean age 25 ± 13 years): 25 had an established diagnosis of WD and 3 were heterozygous relatives without disease. The phenotypes of WD were as follows: 15/25 (60%) with exclusively hepatic manifestation, 8/25 (32%) combination of hepatic and neurological, 1/25 (4.0%) isolated neurological manifestations and 1/25 (4.0%) were pre-symptomatic. We identified 17 ATP7B gene distinct mutations. The pathogenic variants c.3402delC, c.2123T>C and c.3818C>T presented the highest allele frequency, respectively, 25.5%, 15.7% and 15.7%. The majority (80.0%) presented the mutation in compound heterozygosity, 12.0% in homozygosity and 8.0% in simple heterozygosity. The c.2145C>T, c.1552T>C and c.3188C>T variants were considered of undetermined significance; c.2072G>T and c.3071_3072delTG variants were considered probably pathogenic. Regarding the disease phenotype, patients with mutations c.3402delC CG>C and c.2123T>C presented equal distribution of isolated hepatic or hepatic plus neurological phenotype, while c.3818C>T mutation was associated with predominantly hepatic phenotype. Presence of exon 2 deletion was associated with severe neurological manifestations.
ConclusionsThe mutations c.3402delC, c.2123T>C and c.3818C>T were the most prevalent. The c.2145C>T and c.3188C>T variants, considered of undetermined significance, were found in confirmed cases of WD. An important heterogeneity of the ATP7B genotype associated with variation in phenotypic presentation was observed.
