Prenatal genomic testing for ultrasound‐detected fetal structural anomalies

Abstract

In the presence of a fetal structural anomaly, fetal DNA can be obtained through invasive testing (e.g. amniocentesis and chorionic villus sampling) in order to undertake genomic testing to attempt to uncover a unifying genetic diagnosis. There are number of traditional and more novel genomic tests available, which can identify aneuploidy, chromosomal structural variation and/or sequence variants within genes. The cumulative diagnostic yield of such technologies is approximately 25%, 6% and up to 80% in some cohorts for QF-PCR/G-banding karyotype, chromosome microarray and exome sequencing, respectively. Learning objectivesTo understand the technical basis and clinical indications for QF-PCR, G-banding karyotype, chromosome microarray and exome sequencing.To appreciate the potential benefits and challenges associated with exome sequencing. To gain awareness of modern technologies that may be utilised to address recurrence risk, e.g. preimplantation genetic diagnosis and non-invasive prenatal diagnosis. Ethical issuesNot all technologies are currently available across all four nations of the UK, hence challenges are raised regarding healthcare equity. There can be uncertainty around the interpretation of prenatal genomic test results, which can have implications in counselling, particularly regarding termination of pregnancy. Incidental findings may be revealed, which can have implications for counselling and the future health of the fetus and the parents.

Has the introduction of increased genetic prenatal testing affected rates of termination of pregnancy due to fetal abnormality?

“…In recent times, prenatal diagnostics have embraced improved diagnostic tools, including comprehensive genetic analyses such as chromosomal microarray (CMA), trio exome (WES), and genome sequencing (WGS), [1][2][3][4] as well as advanced imaging equipment like ultrasound (UL) and magnetic resonance imaging (MRI). 5,6 Hence, it is plausible to consider whether the quantity and type of prenatal diagnoses and pregnancy terminations due to fetal anomalies (TOPFA) have undergone changes throughout time.…”

“…16,17 The use of CMA and WES/WGS has increased, but internationally there are substantial variations in the recommended indications for their use, and there is in-consistent implementation. 3,18,19 The implementation of these methods has led to an increase in the number of prenatal genetic diagnoses. For instance, replacing karyotyping with CMA led to a 64% rise in the diagnostic yield as a result of detecting disease-causing copy number variation (CNVs) like deletions and duplications.…”

“…In both Denmark and the Netherlands, there was a rise in TOPFA subsequent to the implementation of the national prenatal screening program 16,17 . The use of CMA and WES/WGS has increased, but internationally there are substantial variations in the recommended indications for their use, and there is in‐consistent implementation 3,18,19 . The implementation of these methods has led to an increase in the number of prenatal genetic diagnoses.…”