Exome sequencing for structurally normal fetuses—yields and ethical issues

Hagit Daum*, Tamar Harel, Talya Millo, Avital Eilat, Duha Fahham, Shiri Gershon-Naamat, Adily Basal, Chaggai Rosenbluh, Nili Yanai, Shay Porat, Doron Kabiri, Simcha Yagel, Dan V. Valsky, Orly Elpeleg, Vardiella Meiner, Hagar Mor-Shaked*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


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.

Original languageAmerican English
Pages (from-to)164-168
Number of pages5
JournalEuropean Journal of Human Genetics
Issue number2
StatePublished - Feb 2023

Bibliographical note

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to European Society of Human Genetics.


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