Variantes patogênicas e alteração da expressão em genes candidatos ao espectro óculo-aurículo-vertebral

• Ano de defesa: 2018
• Autor(a) principal: Souza, Malu Zamariolli de [UNIFESP]
• Tipo de documento: Dissertação
• Tipo de acesso: Acesso aberto
• Idioma: por
• Instituição de defesa: Universidade Federal de São Paulo (UNIFESP)
• Palavras-chave em Português: Oculo-auricular-vertebral spectrum; Single nucleotide variants; Candidate genes; Gene expression; OAVS; Espectro óculo-aurículo-vertebral; Variantes de nucleotídeo único; Genes candidatos; Expressão gênica
• Link de acesso: https://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=7044167; https://repositorio.unifesp.br/handle/11600/52320

Objective: To investigate the presence of alterations in the sequence and expression of candidate genes in a cohort of 73 patients diagnosed with oculoauriculovertebral spectrum (OAVS). Methods: Next generation sequencing of exons and untranslated regions (UTRs) from ten candidate genes (YPEL1, MAPK1, CRKL, OTX2, GSC, HMX1, NKX32, MYT1, PUF60 and HOXA2) was performed. Single nucleotide variants (SNVs) were analyzed by several in silico prediction tools and classified into three categories: likely benign, variant of uncertain significance and likely pathogenic. Variants considered as likely pathogenic were validated by Sanger sequencing and their heritability was accessed when parents’ DNA was available. Whole blood expression of the genes containing likely pathogenic variants was evaluated in the patients and compared to a group of control individuals. Results: Six SNVs were considered as likely pathogenic. All of them were in heterozygous state and were localized in the UTRs regions of five sequenced candidate genes (YPEL1, MAPK1, CRKL, OTX2 and MYT1). Variants in the YPEL1, MAPK1, CRKL and OTX2 genes were identified in five unrelated patients, two with variants in YPEL1. In contrast, the variant located in the MYT1 gene was identified in five other unrelated patients. The impact of variants in the YPEL1, MAPK1, CRKL and MYT1 genes on the expression in peripheral blood was verified, however, gene expression analysis showed unmodified transcription levels in the patients when compared to controls. Conclusion: Novel variants in candidate genes were described and they may help to improve the understanding of the complex and unknown etiology of OAVS. The fact that each variant was only identified in one or a few patients supports the hypothesis of the genetic heterogeneity of the spectrum and a probable multifactorial inheritance with different factors involved in the disease, including environmental factors.