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

doi:10.1038/s41431-022-01169-9

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

Faculty of Medicine

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

Abstract

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 language	English
Pages (from-to)	164-168
Number of pages	5
Journal	European Journal of Human Genetics
Volume	31
Issue number	2
DOIs	https://doi.org/10.1038/s41431-022-01169-9
State	Published - Feb 2023

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

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Daum, H., Harel, T., Millo, T., Eilat, A., Fahham, D., Gershon-Naamat, S., Basal, A., Rosenbluh, C., Yanai, N., Porat, S., Kabiri, D., Yagel, S., Valsky, D. V., Elpeleg, O., Meiner, V., & Mor-Shaked, H. (2023). Exome sequencing for structurally normal fetuses—yields and ethical issues. European Journal of Human Genetics, 31(2), 164-168. https://doi.org/10.1038/s41431-022-01169-9

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abstract = "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.",

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

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Daum, H, Harel, T, Millo, T, Eilat, A, Fahham, D, Gershon-Naamat, S, Basal, A, Rosenbluh, C, Yanai, N, Porat, S, Kabiri, D, Yagel, S, Valsky, DV, Elpeleg, O, Meiner, V & Mor-Shaked, H 2023, 'Exome sequencing for structurally normal fetuses—yields and ethical issues', European Journal of Human Genetics, vol. 31, no. 2, pp. 164-168. https://doi.org/10.1038/s41431-022-01169-9

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AU - Daum, Hagit

AU - Harel, Tamar

AU - Millo, Talya

AU - Eilat, Avital

AU - Fahham, Duha

AU - Gershon-Naamat, Shiri

AU - Basal, Adily

AU - Rosenbluh, Chaggai

AU - Yanai, Nili

AU - Porat, Shay

AU - Kabiri, Doron

AU - Yagel, Simcha

AU - Valsky, Dan V.

AU - Elpeleg, Orly

AU - Meiner, Vardiella

AU - Mor-Shaked, Hagar

PY - 2023/2

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N2 - 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.

AB - 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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Exome sequencing for structurally normal fetuses—yields and ethical issues

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