Single gene non‐invasive prenatal screening for autosomal dominant conditions in a high‐risk cohort

Abstract

PurposeTo determine the utility of single gene non‐invasive prenatal screening (NIPS‐SGD) in a high‐risk reproductive genetics clinic.MethodsA clinical pilot for NIPS‐SGD was conducted from March 2020 to November 2021. A NIPS‐SGD panel assessing pathogenic variants in 30 genes was offered to pregnant individuals for the following indications: (1) advanced sperm age ≥40 years, (2) nuchal translucency (NT) ≥ 3.5 mm, (3) fetal anomaly, or (4) family history of a condition covered by the panel. Diagnostic testing was offered concurrently.ResultsNIPS‐SGD was ordered for 253 individuals: 88 (34.8%) for fetal anomalies, 96 (37.9%) for advanced sperm age, 37 (14.6%) for increased NT, and 5 (2.0%) for family history. Among 228 (90.1%) completed tests, 8 (3.5%) were positive. Diagnostic testing for 78 individuals revealed no false positive or negative results. Of 41 (25.9%) individuals who received a molecular diagnosis, 34 (82.9%) were outside the scope of NIPS‐SGD. Positive NIPS‐SGD altered medical management in five cases.ConclusionsNIPS‐SGD in a high‐risk population can lead to earlier prenatal diagnosis, enhanced surveillance, and targeted genetic analysis, but should not replace clinically indicated diagnostic testing. Potential incidental findings include parental diagnoses and misattributed parentage.

Current controversy in prenatal diagnosis: The use of cfDNA to screen for monogenic conditions in low risk populations is ready for clinical use

“…A research group from Boston also concluded that cfDNA testing for monogenic conditions should not replace clinically indicated testing given the high rate of cytogenetic and single gene disorders outside the scope of the panel currently being offered. 33 Whilst no false negative cases have yet to be reported in the literature, as we have seen, follow-up of negative cases has been very poor. This is understandable as these are commercially available tests and follow up is inevitably harder as a third party provider.…”

“…It is not just the conservative British who argue against using this test clinically. A research group from Boston also concluded that cfDNA testing for monogenic conditions should not replace clinically indicated testing given the high rate of cytogenetic and single gene disorders outside the scope of the panel currently being offered 33 …”

Cell-Free DNA Screening for Single-Gene Disorders

“…Most positive results returned in the setting of a known fetal anomaly. 13 These data suggest that single-gene cfDNA screening can be useful in a high-risk cohort. However, diagnostic confirmation is recommended, and such screening cannot replace clinically indicated testing such as cytogenetic testing or diagnostic testing via CVS or amniocentesis as most diagnoses are outside of the scope of single-gene cfDNA screening.…”