Amaurose congênita de Leber: prevalência, correlações genótipo fenótipo e novos achados em uma coorte brasileira

• Ano de defesa: 2020
• Autor(a) principal: Motta, Fabiana Louise Teixeira [UNIFESP]
• Tipo de documento: Tese
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de São Paulo (UNIFESP)
• Palavras-chave em Português: Leber's Congenital Amaurosis; Hereditary Dystrophy Of The Retina; Genetic Profile; Pathogenic Variants; Amaurose Congênita De Leber; Distrofia Hereditária Da Retina; Perfil Genético; Variantes Patogênicas
• Link de acesso: https://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=10186265; https://hdl.handle.net/11600/64859

Purpose: To study the genetic profile of a Brazilian inherited retinal dystrophy cohort, emphasizing cases of Leber congenital amaurosis. Methods: Review of 2,299 medical records and 1,015 genetic tests of patients with inherited retinal dystrophy. Results: In the first part of the study, in which the relative frequency of inherited retinal dystrophy was evaluated, 66 genes associated with these retinopathies were found. More than half of the patients had retinitis pigmentosa (35%) or Stargardt's disease (21%), while patients with Leber congenital amaurosis represented about 9% of the cases. The three most frequently mutated genes were ABCA4, CEP290 (associated with Leber congenital amaurosis), and USH2A. In the second part of the study, we described clinical and molecular findings in a Brazilian cohort with childhood retinal dystrophy, where 80% of cases were patients with Leber congenital amaurosis. One hundred and twenty-three different variants were found in 15 genes, of which 38 variants had never been described before. Furthermore, we have identified and described four new complex alleles (in the CEP290, GUCY2D, RDH12, and NPHP4 genes). The most frequently mutated genes in this cohort were CEP290, RPE65, and CRB1. Furthermore, the most frequent mutations were: c.2991+1655A>G (CEP290), p.Cys948Tyr (CRB1), and deletion of exons 10 to 18 (RPGRIP1). In addition to the aforementioned findings, we also describe three special cases. The first showed the genotype-phenotype correlation associated with the CRB1 gene. Patients with Leber congenital amaurosis had biallelic variants that most dramatically affected the functionality of the protein, unlike what was observed, for example, in patients with retinitis pigmentosa. In the second special case, the pathogenicity reclassification of two variants related to Leber congenital amaurosis in the RPE65 gene was performed. Until now, these variants had been found exclusively in Brazilians. This reclassification directly affects the eligibility of these patients for gene therapy with Luxturna. Finally, a rare case of Leber congenital amaurosis caused by non-Mendelian inheritance (uniparental disomy) identified in this Brazilian cohort was presented in the last special study. Conclusions: The relative frequencies of hereditary retinopathies in Brazil were similar to those found globally. Among the more than 270 genes known to cause inherited retinal dystrophies, 66 genes are responsible for 70% of molecularly characterised cases in this cohort. Mutation in CEP290, RPE65 and CRB1 genes are the cause of 51% of childhood retinal dystrophies, including Leber congenital amaurosis. The identification of the most frequently mutated genes in this cohort enables the development of improved genetic diagnostic tools, targeting these genes enriched in the Brazilian population; this will reduce the cost of first-line genetic testing, thus allowing more people to have access to it. Phenotypic heterogeneity observed in some genes, such as CRB1, can be explained by types of disease-causing mutation. Family segregation analysis is extremely important in determining the bi-parental inheritance of the variants found in recessive cases, as well as in accurate genetic counselling of the individual and family. In this study, trio analysis by next generation sequencing, also used as an alternative to segregation analysis, proved to be an effective tool for detecting uniparental disomy. The reports of new cases and disease-associated variants enriched in a specific population, as presented in this study, can help in establishing genotype-phenotype correlations as well as in the proper classification of variants found in genes related to the disease. These findings, advance our understanding of the biology of inherited retinal disease, and also improve clinical care for the families, providing molecular diagnoses and indication of specialized monitoring and possible treatments.