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Development and clinical validation of a non-invasive test for the chromosome 21 trisomy by analysis of maternal plasma nucleic acids through next generation sequencing

Grant number: 12/01165-0
Support Opportunities:Regular Research Grants
Duration: May 01, 2012 - April 30, 2015
Field of knowledge:Health Sciences - Medicine - Maternal and Child Health
Principal Investigator:José Eduardo Levi
Grantee:José Eduardo Levi
Host Institution: Instituto de Medicina Tropical de São Paulo (IMT). Universidade de São Paulo (USP). São Paulo , SP, Brazil
Associated researchers:Mario Henrique Burlacchini de Carvalho ; Renata Moscolini Romão


Non-invasive and early in pregnancy detection of inherited genetic diseases is an intensively investigated subject in fetal medicine. The most common chromosomal abnormality is the trisomy of chromosome 21, also known as Down's syndrome. At-risk pregnant women are submitted to ultrasound and serum biochemical markers assessment in order to obtain a risk estimative that may justify performing invasive procedures to obtain fetal tissue for confirmation of the syndrome through karyotype determination.In the last 10 years a revolution stroke fetal medicine after the discovery of fetal nucleic acids circulating in maternal plasma. Several applications of this knowledge became available such as the fetal gender determination for both medical and recreational use and RhD investigation for RhD negative women. For genetic diseases with a recognized causative mutation, the paternal affected allele may be detected in the maternal plasma, and now this kind of test is on routine use in some countries for defined pathologies like hemophilia and Huntington's disease. However, the quantitative determination (chromosomal dosage) has proven to be a more difficult task due to the presence of maternal DNA in much higher amount than fetal DNA. Several strategies were envisaged to overcome this obstacle. By obtaining placenta-derived mRNA coded on chromosome 21, the maternal background is excluded. Next, one can use this mRNA to quantify the allelic ratio of chromosome 21 SNPs, that are informative when the fetus is heterozygous.In previous work, our group has identified candidate SNPs in 200 individuals from the Brazilian population. We propose now to use this information in the development of a non-invasive test for the chromosome 21 trisomy. We aim to obtain mRNA from the plasma of pregnant women, amplify several fragments of the selected genes, encompassing the SNPs, and quantify them by employing massive parallel sequencing on the Ion torrent platform. We have already collected a valuable group of 139 paired samples of blood (plasma) and amniotic fluid form at-risk women, with further karyotyping information. This material will be used to validate our assay in a blind clinical trial. (AU)

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