Next generation sequencing and the next generation: how genomics is revolutionizing reproduction.

Abstract

The integration of next generation sequencing (NGS) into clinical care has significantly improved our ability to identify the genetic cause of disease in the postnatal setting. Furthermore, noninvasive prenatal screening for aneuploidy using massively parallel sequencing (MPS) of maternal plasma is the fastest growing genetic or genomic test in the history of medicine. In this 2015 special topic issue, we focus on the application of NGS in the preconceptual, preimplantation, prenatal screening and diagnostic settings. We start by describing advances in carrier screening, which have moved from targeting specific ethnic or racial groups to more comprehensive approaches. We also highlight the challenges, both in obtaining true informed consent, and the difficulties that arise as we detect variants of unclear significance in many more individuals as we screen increasing numbers of genes. How will we cope with the counseling challenges presented? What are the true psychosocial, financial and health impacts of the trend to increase preconceptual and prenatal screening? In this issue we also show how NGS is beginning to affect the selection of pre-implantation embryos. The biggest impact of NGS to date has been the development of prenatal genetic diagnosis and screening based on analysis of cell free DNA (cfDNA) in maternal plasma. For pregnancies known to be at high risk for single gene disorders such as cystic fibrosis and Huntington disease this allows definitive non-invasive prenatal diagnosis (NIPD) based on a maternal blood sample, obviating the requirement for invasive diagnostic testing. Questions raised here include the ease of access and the potential increased uptake of this safe testing, resulting in the use of NIPD for parents to determine the genetic status of their child prior to birth. Whilst this may be useful for conditions in which in utero or early postnatal treatment alleviates the disease course, does it raise ethical issues over carrier screening without consent in minors? To date, the impact of NIPD for single gene disorders on clinical practice has been relatively small, so these questions have not required urgent answers. In contrast, counting of genome-mapped cfDNA fragments in maternal blood as a highly accurate screen for aneuploidy is now in use, mainly in the private sector, worldwide. This has significantly decreased the need for invasive diagnostic testing and has had a major impact on both service delivery and training in invasive procedures. With the increasing use of cfDNA screening we are also recognizing differences in the test performance of autosomal aneuploidies versus sex chromosome aneuploidies, as well as other biologic explanations for discordant false positive results, such as maternal copy number variants (CNVs) and genomic imbalance because of the DNA shed into the maternal circulation by tumors such as uterine leiomyomas. As NGS for autosomal aneuploidy disseminates into general obstetrical care, clear guidelines for parental counseling are required and are proposed here. Analysis of cfDNA for aneuploidy is a screening test that requires invasive (diagnostic) testing for confirmation of an abnormal result. Which invasive test, however, should be performed under these circumstances? As the ‘fetal’ component of circulating cfDNA actually comes from the placenta, Grati and colleagues present information from a large clinical database of mosaic chorionic villus testing results that suggests that different approaches should be taken depending on the chromosome involved. Non-invasive prenatal testing continues to progress rapidly, and here we include a paper that describes the clinical experiences thus far using cfDNA to screen for known microdeletion syndromes. While non-invasive sequencing of the entire fetal genome is not yet ready for routine clinical use, significant progress has been made in the use of whole exome sequencing of DNA extracted from amniocytes, chorionic villi or postmortem samples in fetuses with structural anomalies or Mendelian disorders such as Charcot–Marie–Tooth disease. Whilst there is little doubt that this will increase the diagnostic rate for fetuses presenting with unusual phenotypes, it raises many additional issues, including how to report variants that may not explain the prenatal phenotype, the time taken and costs incurred. As reported by Kalynchuk and colleagues, however, there seems little doubt that expectant parents want as much information as possible.