Exoma na prática clínica: expansão fenotípica, dismorfologia reversa e descoberta de novos genes

• Ano de defesa: 2016
• Autor(a) principal: Migliavacca, Michele Patricia [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: Parallel mass sequencing; Exoma; Genotype; Phenotype; Diagnosis; Sequenciamento paralelo em massa; Genótipo; Fenótipo diagnóstico
• Link de acesso: https://sucupira.capes.gov.br/sucupira/public/consultas/coleta/trabalhoConclusao/viewTrabalhoConclusao.jsf?popup=true&id_trabalho=4125811; http://repositorio.unifesp.br/handle/11600/47514

Purpose: To analyze candidate variants for previous selected patients with Mendelian Diseases using Whole Exome Sequencing (WES). Methods: Patients were obtained from PhenoDB platform and reviewed by a Committee. Those who filled in the selection criteria had the exome sequencing performed by the Illumina HiSeq2000 (Illumina, Inc. San Diego, CA) platform. The data analysis workflow was design to evaluate possible candidate variants using specific computational filters. The ANNOVAR file of each patient was uploaded at the PhenoDb platform being available to the Analysis Committee. Results: Twelve patients that better represented one of the following categories was selected: new gene discovery, phenotypic expansion and reverse dysmorphology. A cohort of six patients were selected to represent the category of new gene discovery, all of them shared the same clinical diagnosis of Gomez-Lopez-Hernandez Syndrome (OMIM 601853, a mendelian disease without a known molecular basis, unfurtunally no candidate variants were found to the moment; a patient with Van den Ende Gupta Syndrome and a SCARF2 homozygous 17bp deletion and a new finding, bilateral sclerocornea, thus extending the phenotype; one patient with severe neonatal ichthyosis and limb malformation, unusual findings in assotiation, with a new mutation at the MBTPS2 responsible for the BRESHECK Syndrome; one patient with a previous clinical diagnosis of Ramos-Arroyo Syndrome and a pathogenic variant at the BCOR gene related to Syndromic Microophtalmya type 2; one brother and one sister with compound heterozygous mutation at the ERCC3 gene, with an overlapping phenotype of Tricothiodystrophy and Xeroderma Pigmentosum, and a patient with a pathogenic variant at HDAC8 gene responsible for Cornelia de Lange type 5 Syndrome. Conclusion: WES is a valid approach to investigated mendelian diseases when a molecular basis is not known, genetic heterogeneity plays a important role or if there is a suggestive mendelian inheritance without a clear diagnosis.