Genetic diagnosis in the fetus

Abstract

Many genetic disorders are detectable in the prenatal period, and the capacity to identify them has increased remarkably as molecular genetic testing techniques continue to improve and become incorporated into clinical practice. The indications for prenatal genetic testing vary widely, including follow-up of an anomaly found by routine ultrasound or maternal aneuploidy screening, a family history of genetic disease, advanced maternal or paternal age, or evaluation of a low-risk pregnancy due to parental concern. The interpretation of genetic variants identified in the prenatal period poses unique challenges due to the lack of ability for deep phenotyping as well as the option to make critical decisions regarding pregnancy continuation and perinatal management. In this review, we address the various modalities currently available and commonly used for genetic testing, including preimplantation genetic testing of embryos, cell-free DNA testing, and diagnostic procedures such as chorionic villous sampling, amniocentesis, or percutaneous umbilical blood sampling, from which samples may be sent for a wide variety of genetic tests. We discuss the difference between these modalities for the genetic diagnosis of a fetus, their strengths and weaknesses, and strategies for their optimal use in order to direct perinatal care.

Figure 1.

Opportunities for prenatal genetic evaluation. IVF, in vitro fertilization; PGT, pre-implantation genetic testing; CVS, chorionic villous sampling; PUBS, percutaneous umbilical blood sampling; cfDNA, cell-free DNA

Figure 2.

Overview of embryonic development and its relevance to prenatal genetic testing. Placental cell lines are demonstrated in italicized font. Testing modalities are encompassed within the text boxes. PGT, pre-implantation genetic testing; cfDNA, cell-free DNA; CVS, chorionic villous sampling. Adapted from [42].