Abstract

Next-generation sequencing as a tool for non-invasive prenatal testing for single gene disorders and aneuploidy

Angela Barrett, Research Fellow, National University of Singapore

Prenatal diagnosis is an essential part of obstetric practice, and genetic diagnosis is currently offered to women carrying a fetus predicted to be at high risk of a chromosomal abnormality, or to couples who are known carriers of a single gene disorder. Prenatal diagnosis of fetal genetic status or aneuploidy depends on the use of invasive diagnostic tests (chorionic villus sampling (CVS) and amniocentesis) to collect a sample of the baby’s genetic material. These invasive procedures carry a small but significant risk of miscarriage of up to 1%. Additionally, these techniques cannot be performed until after eleven weeks of gestation, which may give rise to increased parental anxiety. Because of the risk to the pregnancy, a major goal in prenatal diagnosis has been to develop methods to carry out the tests non-invasively using a maternal blood sample. Next generation sequencing (NGS) is a highly sensitive technique which allows highly accurate non-invasive screening for chromosomal aneuploidy and detection of certain single gene disorders using cell-free DNA. We have developed a non-invasive test for paternally inherited ß-thalassaemia mutations using cfDNA, and are working on tests that can also detect the presence of maternally inherited mutations. In addition, we have successfully demonstrated the utility of NGS for whole chromosome karyotyping of single fetal nucleated red blood cells (FNRBCs), giving a definitive non-invasive prenatal diagnosis of aneuploidy. Non-invasive prenatal tests using cell-free DNA and FNRBCs will be discussed.