High rate of abnormal findings in Prenatal Exome Trio in low risk pregnancies and apparently normal fetuses

Abstract

Objective: Data on the value of exome sequencing in fetuses with no structural anomalies are limited, especially in the early stages of pregnancy and in low risk pregnancies. We investigated the yield of targeted clinical prenatal trio exome sequencing (pES) in pregnancies with and without fetal structural anomalies. Methods:We performed pES in 353 pregnancies: Group 1 included 143 pregnancies with high clinical suspicion for a genetic disease: pregnancies with increased nuchal translucency, ultrasound structural defects, intrauterine growth restriction, polyhydramnios, or effusion/nuchal edema. Group 2 included 210 pregnancies with no notable abnormal fetal ultrasound findings. 2a. Low risk pregnancies with minor ultrasound findings, referred to the geneticist due to mildly increased risk for genetic disease (50); and 2b. Normal pregnancy surveillance (160).Results: Overall, 26 (7.36%) fetal analyses had pathogenic (P)/likely pathogenic (LP) variants. In group 1, 20/143 (13.99%) cases had P/LP variants. In group 2, 6/210 (2.86%) cases were found to have P/LP variants [5/50 in (2a) and 1/160 in (2b)]. Conclusion:These results show a high rate of abnormal findings on pES even in apparently normal pregnancies. Key points What's already known about this topic?� Previous studies demonstrated that exome sequencing contribute a substantial diagnostic information in pregnancies when the fetus present major structural defects and anomalies What does this study add?� This study centers around the inclusion of low risk pregnancies; those with minor ultrasound findings and those with normal pregnancy surveillance. Our findings show that exome sequencing among low risk pregnancies contributed significant and important critical diagnostic information Noy Azoulay has equally contributed as first author.We presented the study at the annual convention of the Israeli Society of Medical Genetics as first spokesperson.

The prevalence of prenatal sonographic findings in postnatal diagnostic exome sequencing performed for neurocognitive phenotypes: A cohort study

“…When performing prenatal ES in cases with no abnormal prenatal phenotype, all variants detected are equivalent to incidental findings. A recently published study reported a diagnostic yield of 0.62% for ES performed in 160 pregnancies with no sonographic anomalies, and a diagnostic yield of 10% among 50 cases with minor sonographic anomalies 27 . To the best of our knowledge, there are currently no other data regarding the yield of unindicated prenatal ES.…”

“…When performing prenatal ES in cases with no abnormal prenatal phenotype, all variants detected are equivalent to incidental findings. A recently published study reported a diagnostic yield of 0.62% for ES performed in 160 pregnancies with no sonographic anomalies, and a diagnostic yield of 10% among 50 cases with minor sonographic anomalies 27. To the best of our knowledge, there are currently no other data regarding the yield of unindicated prenatal ES.Performing ES for fetuses without structural abnormalities detected by US has potential risks and disadvantages, specifically when incidental findings are interpreted for disorders presenting with exclusively postnatal phenotypes.…”

International Society for Prenatal Diagnosis 2022 debate 3—Fetal genome sequencing should be offered to all pregnant patients

“…However, a recent study from Israel reported on a relatively high rate of abnormal findings using ES in low-risk pregnancies and apparently normal fetuses. 17 They described prenatal ES using a panel ofe4500 genes in 353 pregnancies: 143 at high risk and 210 at low risk for a genetic disease. They found a total of 26 (7.4%) pathogenic or likely pathogenic (P/LP) variants.…”

Prenatal exomes and genomes – so much new and so much more to learn

“…24,25 Moreover, at least one study showed that even for fetuses with no observable structural anomalies, P and LP variants can be detected. 26 While this can be concerning, it demonstrates how we can learn from other clinical settings where sequencing is done, and instills optimism about what future research will teach us about currently unknown prenatal presentations of genetic diseases. As highlighted by Liu and Vossaert, new sequencing and data analysis technologies are already used in other clinical scenarios and can be applied to the most elusive prenatal cases.…”

“…Two studies compare results from sequencing on neonates to what could have been detected prenatally if we had more access to sequencing and better strategies to analyze the data and show that many conditions could be diagnosed earlier 24,25 . Moreover, at least one study showed that even for fetuses with no observable structural anomalies, P and LP variants can be detected 26 . While this can be concerning, it demonstrates how we can learn from other clinical settings where sequencing is done, and instills optimism about what future research will teach us about currently unknown prenatal presentations of genetic diseases.…”