The yield of chromosomal microarray analysis (CMA) is well established in structurally normal fetuses (0.4–1.4%). We aimed to determine the incremental yield of exome sequencing (ES) in this population. From February 2017 to April 2022, 1,526 fetuses were subjected to ES; 482 of them were structurally normal (31.6%). Only pathogenic and likely pathogenic (P/LP) variants, per the American College of Medical Genetics and Genomics (ACMG) classification, were reported. Additionally, ACMG secondary findings relevant to childhood were reported. Four fetuses (4/482; 0.8%) had P/LP variants indicating a moderate to severe disease in ATP7B, NR2E3, SPRED1 and FGFR3, causing Wilson disease, Enhanced S-cone syndrome, Legius and Muenke syndromes, respectively. Two fetuses had secondary findings, in RET and DSP. Our data suggest that offering only CMA for structurally normal fetuses may provide false reassurance. Prenatal ES mandates restrictive analysis and careful management combined with pre and post-test genetic counseling.
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Data will be available following a reasonable request. Variants were submitted to ClinVar (SUB9513879). Accession numbers are SCV001572879.1, SCV001572880.1, SCV001572881.1, SCV001572882.1, SCV001572883.1, SCV001437667.1, SCV001437666.1.
The variants described in the article can be found in Table 1. Additional data are available from the corresponding author on reasonable request.
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We would like to thank the genetic counselors and laboratory team for a professional teamwork, and the families for their participation in the study.
There was no financial support in this work.
The authors declare no competing interests.
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This project was approved by the IRB and listed 0189-21-HMO. Any information reported is de-identified. An informed consent was obtained from all participants as required by the IRB.
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Daum, H., Harel, T., Millo, T. et al. Exome sequencing for structurally normal fetuses—yields and ethical issues. Eur J Hum Genet (2022). https://doi.org/10.1038/s41431-022-01169-9