Investigações genéticas em doenças raras: uma contribuição positiva das tecnologias genômicas
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2017-08-09
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Universidade Federal de Goiás
Resumo
Neurological disorders are a group of conditions that manifest early in the development of the
child, so that delayed neuropsychomotor development (ADNPM) and intellectual disability (ID)
can impair cognitive, language, motor and social behavior. The etiology of ID is quite
heterogeneous and prenatal, perinatal and postnatal factors are associated with an increased risk of
this deficiency. However, 30 to 50% of the cases remain with the unknown etiology. In this
context, the main objective of this study was to identify submicroscopic genomic alterations
(<5Mb) by means of microarray chromosomal analysis (CMA) in patients with clinical indication
of ADNPM and/or ID, sent by attending physicians of the state public health network of Goiás. We
analyzed 149 cases of both sexes. Of the total number of patients, 47 had the diagnosis clarified
using cytogenetics by G banding. Of 102 patients with an incomplete diagnosis, 72 agreed to
participate in the present study and, therefore, performed the CMA. The elucidation of the
diagnosis by CMA was possible in 22 patients. Among the results obtained, three rare cases were
selected to compose this thesis. The first case is from a patient in whom a de novo
microduplication of 0.45 Mb in the 5q35.2q35.3 region containing the NSD1 gene was identified.
The effect of the dosing of this gene has been related to Sotos Syndrome and its inverted
phenotype. The second case shows the molecular detection of an absent allele on the X
chromosome and the presence of 28 CGG repeats in FMR1 gene in the present allele. The CMA
showed that the patient had a de novo microdeletion of 4.176 Mb in the Xq27.3-q28 region that
affected 34 genes, including five genes (TMEM185A, TMEM257, FMR1, IDS, and FMR2) that
were directly correlated with ID phenotypes and neurological disorders. The third case is a de novo
microdeletion of 1.59 Mb in the 1p32.3 region involving the DHCR24 gene, which causes a gene
dosage effect influencing the activation of enzymes that cause desmosterolosis, which is a
desmosterol conversion disorder in cholesterol. Thus, the results of this thesis showed the
relevance of the use of the CMA technology to diagnose patients with clinical signs of ADNPM
and/or ID that presented karyotype without alterations, evidencing the importance of this
technology for public health.
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REIS, F. G. Investigações genéticas em doenças raras: uma contribuição positiva das tecnologias genômicas. 2017. 99 f. Tese (Doutorado em Genética e Biologia Molecular) - Universidade Federal de Goiás, Goiânia, 2017.