Counseling Challenges with Variants of Uncertain Significance and Incidental Findings in Prenatal Genetic Screening and Diagnosis

Abstract

Prenatal genetic screening and testing provides prospective parents information about the health of their fetus. It is offered to find or address an increased risk for chromosomal abnormalities or other genetic conditions in the fetus or to identify the cause of fetal structural abnormalities detected by prenatal imaging. Genome-wide tests, such as the already widely-used chromosomal microarray analysis and emerging diagnostic whole exome and whole genome sequencing, have improved the ability to detect clinically significant findings, but have also increased the chance of detecting incidental findings and variants of uncertain significance. There is an extensive ongoing discussion about optimal strategies for diagnostic laboratories to report such findings and for providers to communicate them with patients. While consensus opinions and guidelines are beginning to appear, they often exclude the prenatal setting, due to its unique set of challenging considerations. These include more limited knowledge of the impact of genetic variants when prospectively detected in an ongoing pregnancy, the absence or limitations of detecting clinically recognizable phenotypes at the time of testing and the different decision-making processes that will ensue from testing. In this review, we examine these challenges within the medical ethical framework unique to prenatal care.

Comparing genetic counselor's and patient's perceptions of needs in prenatal chromosomal microarray testing

“…Despite improved detection rate and faster turnaround time, enthusiasm for more widespread use of prenatal CMA testing has been tempered by ethical and counseling challenges . This includes the possibility of laboratories detecting and reporting copy number variants (CNVs) of uncertain clinical significance (VOUS), the detection of CNVs associated with conditions with variable expression or penetrance, and incidental findings including CNVs associated with increased risk for adult‐onset conditions or neuropsychiatric disorders …”

Current landscape of prenatal genetic screening and testing

“…This poses a challenge unique to the prenatal setting where prognostic information may be very limited for patients who may be using it to make reproductive choices (Horn & Parker, ; L. Westerfield et al, ). The uncertainty about the predicted phenotype and lack of precise risk estimate associated with VUS, particularly in the absence of structural abnormalities seen on ultrasound, may also increase anxiety and stress in pregnancy (Reiff et al, ).…”

“…Some pitfalls of WES include longer turnaround times (even though these are becoming shorter with every passing day), high cost, and lack of insurance coverage particularly in the prenatal setting, as well as detection of secondary findings in genes not associated with the fetal phenotype that may presympomatically identify a predisposition to cancer or cardiac disease (Best et al, 2018;Mone, Quinlan-Jones, & Kilby, 2018). However, by far one of the major challenges with new technologies such as WES as well as CMA is the detection of VUS and the difficulty of interpreting these results in a prenatal setting (Westerfield et al, 2015;Westerfield, Darilek, & van den Veyver, 2014). Interpretation of a VUS is highly dependent on the phenotypic information, which is often incomplete, or in some situation incorrect, due to limitations of prenatal imaging (Abou Tayoun et al, 2018;Wou, Chung, & Wapner, 2018).…”

Pre- and post-test genetic counseling for chromosomal and Mendelian disorders

“…1, 94,95 Specific concerns include the possibility of detecting copy number variants (CNVs) of uncertain clinical significance (VOUS), the detection of CNVs associated with conditions with variable expression or penetrance, and incidental findings including CNVs associated with an increased risk for adult-onset conditions or neuropsychiatric disorders. 95, 96, 97 These findings complicate pre-test counseling and when detected, cause significant distress and difficulty with decision-making. 2 …”

“…95 Careful pre-test counseling can help couples understand the types of results available from prenatal CMA testing, and the uncertainties associated with many results. Unfortunately, uncertainty will be persistent as the genome is assayed more finely.…”