Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Exome sequencing for structurally normal fetuses—yields and ethical issues

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.

This is a preview of subscription content, access via your institution

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Fig. 1: Schemes presenting our current knowledge of the yield of CMA and ES in prenatal diagnosis, and study design and findings.

Data availability

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.

Code availability

The variants described in the article can be found in Table 1. Additional data are available from the corresponding author on reasonable request.

References

  1. Al-Dewik N, Mohd H, Al-Mureikhi M, Ali R, Al-Mesaifri F, Mahmoud L, et al. Clinical exome sequencing in 509 Middle Eastern families with suspected Mendelian diseases: the Qatari experience. Am J Med Genet A. 2019;179:927–35.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  2. Lee H, Deignan JL, Dorrani N, Strom SP, Kantarci S, Quintero-Rivera F, et al. Clinical exome sequencing for genetic identification of rare Mendelian disorders. JAMA. 2014;312:1880–7.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Hengel H, Buchert R, Sturm M, Haack TB, Schelling Y, Mahajnah M, et al. First-line exome sequencing in Palestinian and Israeli Arabs with neurological disorders is efficient and facilitates disease gene discovery. Eur J Hum Genet. 2020;28:1034–43.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Lord J, McMullan DJ, Eberhardt RY, Rinck G, Hamilton SJ, Quinlan-Jones E, et al. Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study. Lancet. 2019;393:747–57.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Petrovski S, Aggarwal V, Giordano JL, Stosic M, Wou K, Bier L, et al. Whole-exome sequencing in the evaluation of fetal structural anomalies: a prospective cohort study. Lancet. 2019;393:758–67.

    Article  PubMed  CAS  Google Scholar 

  6. Mellis R, Oprych K, Scotchman E, Hill M, Chitty LS. Diagnostic yield of exome sequencing for prenatal diagnosis of fetal structural anomalies: a systematic review and meta-analysis. Prenat Diagn. 2022;42:662–85.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Pauta M, Martinez-Portilla RJ, Borrell A. Diagnostic yield of exome sequencing in fetuses with multisystem malformations: systematic review and meta-analysis. Ultrasound Obstet Gynecol. 2022;59:715–22.

    Article  PubMed  CAS  Google Scholar 

  8. Stern S, Hacohen N, Meiner V, Yagel S, Zenvirt S, Shkedi-Rafid S, et al. Universal chromosomal microarray analysis reveals high proportion of copy number variants in low risk pregnancies. Ultrasound Obstet Gynecol. 2021;57:813–20.

    Article  PubMed  CAS  Google Scholar 

  9. Sagi-Dain L, Cohen Vig L, Kahana S, Yacobson S, Tenne T, Agmon-Fishman I, et al. Chromosomal microarray vs. NIPS: analysis of 5541 low-risk pregnancies. Genet Med. 2019;21:2462–7.

    Article  PubMed  Google Scholar 

  10. Moshonov R, Hod K, Azaria B, Abadi-Korek I, Berger R, Shohat M. Benefit versus risk of chromosomal microarray analysis performed in pregnancies with normal and positive prenatal screening results: a retrospective study. PLoS ONE. 2021;16:e0250734.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Wapner RJ, Martin CL, Levy B, Ballif BC, Eng CM, Zachary JM, et al. Chromosomal microarray versus karyotyping for prenatal diagnosis. N Engl J Med. 2012;367:2175–84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Zhang Z, Hu T, Wang J, Hu R, Li Q, Xiao L, et al. Pregnancy outcomes of fetuses with congenital heart disease after a prenatal diagnosis with chromosome microarray. Prenat Diagn. 2022;42:79–86.

    Article  PubMed  CAS  Google Scholar 

  13. Tzadikevitch Geffen K, Singer A, Maya I, Sagi-Dain L, Khayat M, Ben-Shachar S, et al. Chromosomal microarray should be performed for cases of fetal short long bones detected prenatally. Arch Gynecol Obstet. 2021;303:85–92.

    Article  PubMed  CAS  Google Scholar 

  14. Hochner H, Daum H, Douiev L, Zvi N, Frumkin A, Macarov M, et al. Information women choose to receive about prenatal chromosomal microarray analysis. Obstet Gynecol. 2020;135:149–57.

    Article  PubMed  Google Scholar 

  15. Pfundt R, Del Rosario M, Vissers LELM, Kwint MP, Janssen IM, de Leeuw N, et al. Detection of clinically relevant copy-number variants by exome sequencing in a large cohort of genetic disorders. Genet Med. 2017;19:667–75.

    Article  PubMed  CAS  Google Scholar 

  16. Yauy K, de Leeuw N, Yntema HG, Pfundt R, Gilissen C. Accurate detection of clinically relevant uniparental disomy from exome sequencing data. Genet Med. 2020;22:803–8.

    Article  PubMed  CAS  Google Scholar 

  17. Kadalayil L, Rafiq S, Rose-Zerilli MJ, Pengelly RJ, Parker H, Oscier D, et al. Exome sequence read depth methods for identifying copy number changes. Brief Bioinform. 2015;16:380–92.

    Article  PubMed  CAS  Google Scholar 

  18. Kalia SS, Adelman K, Bale SJ, Chung WK, Eng C, Evans JP, et al. Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. Genet Med. 2017;19:249–55.

    Article  PubMed  Google Scholar 

  19. Lazarin GA, Hawthorne F, Collins NS, Platt EA, Evans EA, Haque IS. Systematic classification of disease severity for evaluation of expanded carrier screening panels. PLoS ONE. 2014;9:e114391.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Dzieżyc K, Karliński M, Litwin T, Członkowska A. Compliant treatment with anti-copper agents prevents clinically overt Wilson’s disease in pre-symptomatic patients. Eur J Neurol. 2014;21:332–7.

    Article  PubMed  Google Scholar 

  21. Hull S, Arno G, Sergouniotis PI, Tiffin P, Borman AD, Chandra A, et al. Clinical and molecular characterization of enhanced S-cone syndrome in children. JAMA Ophthalmol. 2014;132:1341–9.

    Article  PubMed  Google Scholar 

  22. Ferraz Sallum JM, Godoy J, Kondo A, Kutner JM, Vasconcelos H, Maia A. The first gene therapy for RPE65 biallelic dystrophy with voretigene neparvovec-rzyl in Brazil. Ophthalmic Genet. 2022;1–5. Online ahead of print.

  23. Kraft SA, Duenas D, Wilfond BS, Goddard KAB. The evolving landscape of expanded carrier screening: challenges and opportunities. Genet Med. 2019;21:790–7.

    Article  PubMed  Google Scholar 

  24. Öwall L, Kreiborg S, Dunø M, Hermann NV, Darvann TA, Hove H. Phenotypic variability in Muenke syndrome-observations from five Danish families. Clin Dysmorphol. 2020;29:1–9.

    Article  PubMed  Google Scholar 

  25. González-Del Angel A, Estandía-Ortega B, Alcántara-Ortigoza MA, Martínez-Cruz V, Gutiérrez-Tinajero DJ, Rasmussen A, et al. Expansion of the variable expression of Muenke syndrome: hydrocephalus without craniosynostosis. Am J Med Genet A. 2016;170:3189–96.

    Article  PubMed  Google Scholar 

  26. Järvelä I, Määttä T, Acharya A, Leppälä J, Jhangiani SN, Arvio M, et al. Exome sequencing reveals predominantly de novo variants in disorders with intellectual disability (ID) in the founder population of Finland. Hum Genet. 2021;140:1011–29.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Monies D, Abouelhoda M, Assoum M, Moghrabi N, Rafiullah R, Almontashiri N, et al. Lessons learned from large-scale, first-tier clinical exome sequencing in a highly Consanguineous population. Am J Hum Genet. 2019;104:1182–201.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Veltman JA, Brunner HG. De novo mutations in human genetic disease. Nat Rev Genet. 2012;13:565–75.

    Article  PubMed  CAS  Google Scholar 

  29. Zhytnik L, Peters M, Tilk K, Simm K, Tõnisson N, Reimand T, et al. From late fatherhood to prenatal screening of monogenic disorders: evidence and ethical concerns. Hum Reprod Update. 2021;27:1056–85.

    Article  PubMed  Google Scholar 

  30. Yatsenko AN, Turek PJ. Reproductive genetics and the aging male. J Assist Reprod Genet. 2018;35:933–41.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Orioli IM, Castilla EE, Scarano G, Mastroiacovo P. Effect of paternal age in achondroplasia, thanatophoric dysplasia, and osteogenesis imperfecta. Am J Med Genet. 1995;59:209–17.

    Article  PubMed  CAS  Google Scholar 

  32. Goriely A, McGrath JJ, Hultman CM, Wilkie AO, Malaspina D. “Selfish spermatogonial selection”: a novel mechanism for the association between advanced paternal age and neurodevelopmental disorders. Am J Psychiatry. 2013;170:599–608.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Friedman JM. Genetic disease in the offspring of older fathers. Obstet Gynecol. 1981;57:745–9.

    PubMed  CAS  Google Scholar 

  34. Janecka M, Mill J, Basson MA, Goriely A, Spiers H, Reichenberg A, et al. Advanced paternal age effects in neurodevelopmental disorders-review of potential underlying mechanisms. Transl Psychiatry. 2017;7:e1019.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  35. Groeneweg JA, van der Zwaag PA, Olde Nordkamp LR, Bikker H, Jongbloed JD, Jongbloed R, et al. Arrhythmogenic right ventricular dysplasia/cardiomyopathy according to revised 2010 task force criteria with inclusion of non-desmosomal phospholamban mutation carriers. Am J Cardiol. 2013;112:1197–206.

    Article  PubMed  Google Scholar 

  36. Makri A, Akshintala S, Derse-Anthony C, Widemann B, Stratakis CA, Glod J, et al. Multiple endocrine neoplasia type 2B presents early in childhood but often is undiagnosed for years. J Pediatr. 2018;203:447–9.

    Article  PubMed  PubMed Central  Google Scholar 

  37. Lazzarini E, Jongbloed JD, Pilichou K, Thiene G, Basso C, Bikker H, et al. The ARVD/C genetic variants database: 2014 update. Hum Mutat. 2015;36:403–10.

    Article  PubMed  CAS  Google Scholar 

  38. Ben-Chetrit E. Familial Mediterranean fever (FMF) and renal AA amyloidosis-phenotype-genotype correlation, treatment and prognosis. J Nephrol. 2003;16:431–4.

    PubMed  CAS  Google Scholar 

  39. Vaknin N, Azoulay N, Tsur E, Tripolszki K, Urzi A, Rolfs A, et al. High rate of abnormal findings in Prenatal Exome Trio in low risk pregnancies and apparently normal fetuses. Prenat Diagn. 2022;42:725–35.

    Article  PubMed  CAS  Google Scholar 

  40. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would like to thank the genetic counselors and laboratory team for a professional teamwork, and the families for their participation in the study.

Funding

There was no financial support in this work.

Author information

Authors and Affiliations

Authors

Contributions

Conceptualization—HMS, HD, TH, Formal analysis—HMS, OE, VM, TM, Resources—CR, AE, DF, Software—SGN, AB, Writing—original draft—HMS, HD, Writing—review and editing—TH, NY, SP, DK, SY, TM, DVV.

Corresponding authors

Correspondence to Hagit Daum or Hagar Mor-Shaked.

Ethics declarations

Competing interests

The authors declare no competing interests.

Ethics approval and consent to participate

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.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

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

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41431-022-01169-9

Search

Quick links