Abstract
Exome sequencing has been increasingly implemented in prenatal genetic testing for fetuses with morphological abnormalities but normal rapid aneuploidy detection and microarray analysis. We present a retrospective study of 90 fetuses with different abnormal ultrasound findings, in which we employed the singleton exome sequencing (sES; 75 fetuses) or to a lesser extent (15 fetuses) a multigene panel analysis of 6713 genes as a primary tool for the detection of monogenic diseases. The detection rate of pathogenic or likely pathogenic variants in this study was 34.4%. The highest diagnostic rate of 56% was in fetuses with multiple anomalies, followed by cases with skeletal or renal abnormalities (diagnostic rate of 50%, respectively). We report 20 novel disease-causing variants in different known disease-associated genes and new genotype–phenotype associations for the genes KMT2D, MN1, CDK10, and EXOC3L2. Based on our data, we postulate that sES of fetal index cases with a concurrent sampling of parental probes for targeted testing of the origin of detected fetal variants could be a suitable tool to obtain reliable and rapid prenatal results, particularly in situations where a trio analysis is not possible.
Highlights
Structural fetal abnormalities are detected by prenatal ultrasound in ~3–4% of pregnancies [1], and 8.4–18.2% of these cases are caused by an abnormal karyotype [2, 3]
The cases included in this study have been selected of all consecutive fetuses with normal Rapid Aneuploidy Detection (RAD) and microarray testing undergoing prenatal genetic testing by referring gynecologists according to their best practice based on clinical assessment of fetal ultrasound phenotype suspicious of monogenic cause
We reported only pathogenic or likely pathogenic variants (Table 2)
Summary
Structural fetal abnormalities are detected by prenatal ultrasound in ~3–4% of pregnancies [1], and 8.4–18.2% of these cases are caused by an abnormal karyotype [2, 3]. Along with the increased genetic detection rate, prenatal whole-exome sequencing (WES) can reveal new and/or unexpected associations between fetal phenotypes and identified variants, considerably extending the spectrum of prenatal manifestations of disease-causing variants in specific genes. Despite the ongoing discussions regarding indications for exome sequencing in a prenatal setting [12,13,14], the challenges of interpreting variants of unknown significance or of de novo variants in potential candidate genes, and strategies for managing secondary findings, this method has already become an important diagnostic tool in pregnancies with fetal abnormalities
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