Abstract
Prenatal ultrasound (US) abnormalities often pose a clinical dilemma and necessitate facilitated investigations in the search of diagnosis. The strategy of pursuing fetal whole-exome sequencing (WES) for pregnancies complicated by abnormal US findings is gaining attention, but the reported diagnostic yield is variable. In this study, we describe a tertiary center’s experience with fetal WES from both terminated and ongoing pregnancies, and examine the clinical factors affecting the diagnostic rate. A total of 45 consecutive families of Jewish descent were included in the analysis, for which clinical fetal WES was performed under either single (fetus only), trio (fetus and parents) or quatro (two fetuses and parents) design. Except one, all families were non-consanguineous. In 41 of the 45 families, WES was sought following abnormal fetal US findings, and 18 of them had positive relevant family history (two or more fetuses with US abnormalities, or single fetus with US abnormalities and an affected parent). The overall diagnostic yield was 28.9% (13/45 families), and 31.7% among families with fetal US abnormalities (13/41). It was significantly higher in families with prenatal US abnormalities and relevant family history (10/18, 55.6%), compared to families with prenatal US abnormal findings and lack of such history (3/23, 13%) (p = 0.004). WES yield was relatively high (42.9–60%) among families with involvement of brain, renal or musculoskeletal US findings. Taken together, our results in a real-world setting of genetic counseling demonstrates that fetal WES is especially indicated in families with positive family history, as well as in fetuses with specific types of congenital malformation.
Highlights
Recent years have seen the growing implementation of next-generation sequencing (NGS) techniques into widespread clinical use, revolutionizing the diagnostic odyssey for many families with monogenic disorders (Yang et al, 2013; Stranneheim and Wedell, 2016)
The pregnant women were at an average gestational age of 23 ± 7.5 weeks at first genetic counseling in our clinic
Amniocentesis was performed to exclude mutation in the fetus, due to option of germline mosaicism. In this retrospective study, representing a clinical experience and practice within a tertiary referral hospital in Israel, we investigated the yield of fetal whole-exome sequencing (WES), from terminated and ongoing pregnancies
Summary
Recent years have seen the growing implementation of next-generation sequencing (NGS) techniques into widespread clinical use, revolutionizing the diagnostic odyssey for many families with monogenic disorders (Yang et al, 2013; Stranneheim and Wedell, 2016). In the Prenatal Assessment of Genomes and Exomes (PAGE) study, which included exome sequencing in 610 fetuses (and 1202 parental samples) with structural anomalies detected by US, a diagnostic genetic variant was found in 8.5% of the fetuses, and additional 3.9% of fetuses had variant of unknown significance (VUS) with potential clinical usefulness (Lord et al, 2019). In another WES study of fetuses with structural anomalies, diagnostic rate of 10.3% among 234 fetus-parents trios was reported (Petrovski et al, 2019)
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