Objective Conventional genetic tests (quantitative fluorescent‐PCR [QF‐PCR] and single nucleotide polymorphism‐array) only diagnose ~40% of fetuses showing ultrasound abnormalities. Rapid exome sequencing (rES) may improve this diagnostic yield, but includes challenges such as uncertainties in fetal phenotyping, variant interpretation, incidental unsolicited findings, and rapid turnaround times. In this study, we implemented rES in prenatal care to increase diagnostic yield. Methods We prospectively studied 55 fetuses. Inclusion criteria were: (a) two or more independent major fetal anomalies, (b) hydrops fetalis or bilateral renal cysts alone, or (c) one major fetal anomaly and a first‐degree relative with the same anomaly. In addition to conventional genetic tests, we performed trio rES analysis using a custom virtual gene panel of ~3850 Online Mendelian Inheritance in Man (OMIM) genes. Results We established a genetic rES‐based diagnosis in 8 out of 23 fetuses (35%) without QF‐PCR or array abnormalities. Diagnoses included MIRAGE (SAMD9), Zellweger (PEX1), Walker‐Warburg (POMGNT1), Noonan (PTNP11), Kabuki (KMT2D), and CHARGE (CHD7) syndrome and two cases of Osteogenesis Imperfecta type 2 (COL1A1). In six cases, rES diagnosis aided perinatal management. The median turnaround time was 14 (range 8‐20) days. Conclusion Implementing rES as a routine test in the prenatal setting is challenging but technically feasible, with a promising diagnostic yield and significant clinical relevance.

Background: Adding rapid exome sequencing (rES) to conventional genetic tests improves the diagnostic yield of pregnancies showing ultrasound abnormalities but also carries a higher chance of unsolicited findings. We evaluated how rES, including pre-and post-test counseling, was experienced by parents investigating its impact on decision-making and experienced levels of anxiety.Methods: A mixed-methods approach was adopted. Participating couples (n = 46) were asked to fill in two surveys (pre-test and post-test counseling) and 11 couples were approached for an additional interview.Results: All couples accepted the rES test-offer with the most important reason for testing emphasizing their hope of finding an underlying diagnosis that would aid decision-making. The actual impact on decision-making was low, however, since most parents decided to terminate the pregnancy based on the major and multiple fetal ultrasound anomalies and did not wait for their rES results. Anxiety was elevated for most participants and decreased over time. Conclusion:Major congenital anomalies detected on ultrasound seem to have more impact on prenatal parental decision-making and anxiety then the offer and results of rES. However, the impact of rES on reproductive decision-making and experienced anxiety requires further investigation, especially in pregnancies where less (severe) fetal anomalies are detected on ultrasound. Key pointsWhat is already known about this topic? � Adding exome sequencing to conventional prenatal genetic tests improves the diagnostic yield.� Prenatal rapid exome sequencing (rES) with a 2-week turnaround time is feasible.