| Grant number: | 15/11998-8 |
| Support Opportunities: | Scholarships abroad - Research Internship - Doctorate |
| Start date: | September 01, 2015 |
| End date: | October 31, 2015 |
| Field of knowledge: | Biological Sciences - Genetics - Human and Medical Genetics |
| Principal Investigator: | Maria Rita dos Santos e Passos Bueno |
| Grantee: | Carolina Malcher Amorim de Carvalho Silva |
| Supervisor: | Iwijn de Vlaminck |
| Host Institution: | Instituto de Biociências (IB). Universidade de São Paulo (USP). São Paulo , SP, Brazil |
| Institution abroad: | Cornell University, United States |
| Associated to the scholarship: | 13/14996-0 - Detection of fetal genetic disorders through non-invasive prenatal testing using next-generation sequencing, BP.DR |
Abstract Chromosomal abnormalities account for about 6% of cases of congenital anomalies, and aneuploidies are the most common chromosomal abnormality in humans. Among the autosomal aneuploidies, the most prevalent are the Down syndrome (Trisomy 21), Edwards (Trisomy 18) and Patau syndromes (Trisomy 13). The discovery of cell-free fetal DNA (cffDNA) in the maternal circulation allowed several studies focusing on prenatal diagnosis by non-invasive detection of cffDNA in the maternal plasma which is currently done for some traits, such as fetal sex determination and Rh factor and, more recently, detection of aneuploidy. However, the use of cffDNA to diagnose monogenic diseases is still in its initial state. One of the major limitations to successfully detect the cffDNA is the sensitivity of the methods, that might be overcome by the use of next-generation sequencing together with bioinformatic tools. The aim of this work is to implement a noninvasive prenatal detection test of genetic disorders in fetuses using these approaches. For trisomies, the chromosomes 21 and 18 will be tested, and for monogenic disease, Duchenne muscular dystrophy. In order to do this, probes for detecting both non-polymorphic and polymorphic loci will be used for estimating both trisomy and the fraction of cffDNA. The detection of trisomies will be performed through the sequencing counts of non-polymorphic loci on the chromosomes of interest, whilst for the determination of the fraction of cffDNA present in maternal plasma, informative SNPs for the Brazilian population will be used across autosomes other than the chromosomes of interest. The cffDNA fraction is an important factor for the correct estimation of trisomies, since the increase of the reads from the chromosomes of interest is proportional to the fraction of cffDNA present in the sample. For the cffDNA fraction estimation, a proof-of-concept will be performed using high-coverage sequencing data of in-silico generated samples with different fetal fractions. For our group, one of the challenges of this project is the bioinformatic analysis, which has to allow the proper discrimination of the cffDNA, with very few copies, within the maternal DNA. Therefore, our BEPE proposal is to use SNPs inferred from targeted sequencing data for the estimation of cffDNA fraction based on a statistical model. | |
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