PREIMPLANTATION GENETIC TESTING: Non-invasive prenatal testing for aneuploidy, copy-number variants and single-gene disorders

Abstract

<jats:p>The discovery of cell-free fetal DNA (cffDNA) in maternal plasma has enabled a paradigm shift in prenatal testing, allowing for safer, earlier detection of genetic conditions of the fetus. Non-invasive prenatal testing (NIPT) for fetal aneuploidies has provided an alternative, highly efficient approach to first-trimester aneuploidy screening, and since its inception has been rapidly adopted worldwide. Due to the genome-wide nature of some NIPT protocols, the commercial sector has widened the scope of cell-free DNA (cfDNA) screening to include sex chromosome aneuploidies, rare autosomal trisomies and sub-microscopic copy number variants. These developments may be marketed as “expanded NIPT” or “NIPT Plus”, and bring with them a plethora of ethical and practical considerations. Concurrently, cfDNA tests for single gene disorders, termed non-invasive prenatal diagnosis (NIPD), have been developed for an increasing array of conditions but are less widely available. Despite the fact that all these tests utilise the same biomarker, cfDNA, there is considerable variation in key parameters such as sensitivity, specificity and positive predictive value depending on what the test is for. The distinction between diagnostics and screening has become blurred, and there is a clear need for the education of physicians and patients regarding the technical capabilities and limitations of these different forms of testing. Furthermore, there is a requirement for consistent guidelines that apply across health sectors, both public and commercial, to ensure that tests are validated and robust, and that careful and appropriate pre-test and post-test counselling is provided by professionals who understand the tests offered.</jats:p>

Current Overview of Osteogenesis Imperfecta

“…Since 2011, several companies have begun to provide NIPT for aneuploidies worldwide, which has now been introduced as a common option for prenatal diagnosis in many countries [ 63 ]. This concept has been adopted for single-gene disorders as well, as noninvasive prenatal diagnosis (NIPD) has also been developed over the last few decades; however, the progress is slower than that of NIPT for aneuploidy screening due to a much smaller market share and technical difficulties [ 64 , 65 ].…”

“…Firstly, NIPD has been developed for autosomal dominant disorders, such as achondroplasia and thanatophoric dysplasia, that are either paternally inherited or occur due to de novo mutations [ 66 ]. In these cases, the presence or absence of the mutation in maternal plasma can be diagnostic for the foetal condition [ 65 ]. NIPD has also been used for paternal exclusion testing for autosomal recessive conditions, including cystic fibrosis, when the father and mother carry different mutations [ 65 ].…”

Non‐invasive prenatal testing: clinical utility and ethical concerns about recent advances

“…Whereas prenatal microarray testing of amniotic fluid in Australia is primarily used in the context of a fetal structural abnormality, higher resolution NIPT could become a general screening test. This would, however, increase both the number of variants of uncertain significance and the likelihood that they are detected in an apparently phenotypically normal fetus 3,10 …”

PREIMPLANTATION GENETIC TESTING: 30 years of preimplantation genetic testing

“…Thirty years ago, it was anticipated that early noninvasive methods of diagnosing inherited disease from trophoblast cells recovered from the lower pole of the uterus or from cell-free foetal DNA in maternal blood would be developed and would, within a few years, replace PGT because of the expense and difficulty of the IVF process especially for fertile couples. In the event, it would be over two decades later following the development of NGS that non-invasive prenatal testing (NIPT) for common aneuploidies became possible and only now that this approach is being extended to genome-wide aneuploidies, microdeletion syndromes and some common monogenic diseases (Shaw et al 2020).…”