Doutorado em Genética e Biologia Molecular (ICB)
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Item Investigação genômica em pacientes com deficiência intelectual ou atraso global do desenvolvimento assistidos na rede pública de saúde do estado de Goiás(Universidade Federal de Goiás, 2022-02-21) D’Ávila, Ana Julia da Cunha Leite; Minasi, Lysa Bernardes; http://lattes.cnpq.br/9057708164796074; Cruz, Aparecido Divino da; http://lattes.cnpq.br/7868817504129985; Cruz, Aparecido Divino da; Silva, Claudio Carlos da; Gigonzac, Thais Cidália Vieira; Costa, Emilia Oliveira Alves; Silva, Daniela de Melo eIntellectual Disability (ID) is a complex and heterogeneous clinical condition that affects about 1 to 3% of children and adolescents worldwide, and that can be caused by a variety of environmental and/or genetic factors. There are a variety of human genetic variants already identified for ID, from small variants to larger structural variants that affect thousands to millions of nucleotides. GTG banding karyotyping and microarray chromosome analysis (CMA) are often used to identify the genetic causes of ID, especially in cases Where the clinical evaluation indicates the syndromic form of ID. The use of next generation sequencing technologies for the diagnosis of ID has made it possible to expand the detection of new mutations and new genes associated with ID. The aim of this study was to perform total exome sequencing with gene panel analysis for intellectual disability, in patients who presented karyotype without structural and/or numerical alterations and did not present pathogenic copy number variations (CNVS) in the CMA. A retrospective cohort of 369 patients of both sexes with clinical indications of DI and/or global developmental delay was evaluated in the study. Peripheral blood samples were collected to perform cytogenetic analysis and gene sequencing. GTG banding was performed for all patients following the standard protocol. CMA was performed for patients who did not present structural and/or numerical alterations in the karyotype. Genomic DNA was isolated from patients and their biological parents in order to determine the origin of the CNVs found. Cases that were not diagnosed after performing the karyotype and CMA were referred for exome sequencing with gene panel analysis for intellectual disability, which encompassed 1,252 genes. With the karyotype, it was possible to identify chromosomal alterations in 34.7% (128/369) of the patients. CMA was performed in 83 patients who had results with no alterations in karyotype (46,XX or 46,XY) with a diagnosis rate of 21.7% (18/83). Exome sequencing for target genes was performed in 19 trios of families that had negative results in previous methodologies. Gene panel analysis of exome data identified mutations in 63.1% (12/19) of cases, of which 75% (9/12) were pathogenic variants, 8.3% (1/12) probably pathogenic and in 16.7% (2/2) VUS. Of the total variants identified, 75% (9/12) were de novo mutations and 25% (3/12) had mutations inherited from healthy parents. The most prevalent variants were missense-type mutations (66.7%) followed by nonsense-type mutations 16.7%), frameshift (8.3%) and loss CNV (8.3%). With the three methodologies applied, it was possible to identify the genetic causes of ID in 42.3% (156/369) of the patients. In conclusion, our results show different methodologies that can be used for the genetic diagnosis of ID and that exome sequencing with gene panel analysis provides an efficient diagnostic strategy when combined with clinical and laboratory screening.Item Evidência do aumento de desvios mendelianos mediante análise transgeracional de mutações germinativas em população exposta à radiação ionizante de Césio-137(Universidade Federal de Goiás, 2022-08-12) Oliveira, Lorraynne Guimarães; Costa, Emília Oliveira Alves; http://lattes.cnpq.br/2332660855010816; Cruz, Aparecido Divino da; http://lattes.cnpq.br/7868817504129985; Silva, Daniela de Melo e; Silva, Claudio Carlos da; Dias, Renata de Oliveira; Leito Filho, Hugo Pereira; Cruz, Aparecido Divino daOn September 13th, 1987, the largest radiological accident in urban areas occurred in Goiânia, Goiás (Brazil), resulting in human, animal, plant and environmental exposure by Cesium-137. The mutagenic effects on the germline of people exposed to ionizing radiation are of particular concern, as the risk of inherited disorders can be increased. Single Nucleotide Variants are the most common form of human genetic variation and occur in greater abundance in a non-coding region and in recent years, several technologies have been developed to identify these variants. One of these technologies is Next-Generation Sequencing, which offers greater amounts of data, shorter sequencing times and reduced costs. The objective of this work is to establish the spectrum and frequency / rate of base de novo substitutions of germ origin from the trio's new generation sequencing data, corresponding to an F1 generation child and his biological parents, accidentally exposed to high and low doses of IR of cesium-137, contributing to knowledge about the biological effects of exposure to ionizing radiation. Considering case and control, the results of 38 parents, and an offspring of 14 children born from the exposed group and 5 children from the unexposed population were included. Exposed individuals had ~39% increase in global mean DMs compared to controls. Exposed mothers had ~44% increase in global mean DMs compared to controls. The A:T>C:G mutation was the one that showed the greatest statistically significant increase in occurrence in the offspring of exposed individuals. Transition replacement rates were higher than transversions in the offspring of cases and controls, but the difference is not statistically significant. In conclusion, with the methodology and biomarkers used, it was possible to identify the origin of mutation in the parents, as well as the type of substitution and to inform which variant was mutated, it was also possible to detect the frequency of the germline mutation in DM which made it possible to retrospectively study this population exposed to IR.