Prenatal exome sequencing in 65 fetuses with abnormality of the corpus callosum: contribution to further diagnostic delineation

Abstract

Purpose

Abnormality of the corpus callosum (AbnCC) is etiologically a heterogeneous condition and the prognosis in prenatally diagnosed cases is difficult to predict. The purpose of our research was to establish the diagnostic yield using chromosomal microarray (CMA) and exome sequencing (ES) in cases with prenatally diagnosed isolated (iAbnCC) and nonisolated AbnCC (niAbnCC).

Methods

CMA and prenatal trio ES (pES) were done on 65 fetuses with iAbnCC and niAbnCC. Only pathogenic gene variants known to be associated with AbnCC and/or intellectual disability were considered.

Results

pES results were available within a median of 21.5 days (9–53 days). A pathogenic single-nucleotide variant (SNV) was identified in 12 cases (18%) and a pathogenic CNV was identified in 3 cases (4.5%). Thus, the genetic etiology was determined in 23% of cases. In all diagnosed cases, the results provided sufficient information regarding the neurodevelopmental prognosis and helped the parents to make an informed decision regarding the outcome of the pregnancy.

Conclusion

Our results show the significant diagnostic and prognostic contribution of CMA and pES in cases with prenatally diagnosed AbnCC. Further prospective cohort studies with long-term follow-up of the born children will be needed to provide accurate prenatal counseling after a negative pES result.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Fig. 1: Flowchart of included fetuses.

References

  1. 1.

    Edwards TJ, Sherr EH, Barkovich AJ, Richards LJ. Clinical, genetic and imaging findings identify new causes for corpus callosum development syndromes. Brain. 2014;137:1579–1613.

    Article  Google Scholar 

  2. 2.

    Glass HC, Shaw GM, Ma C, Sherr EH. Agenesis of the corpus callosum in California 1983-2003: a population-based study. Am J Med Genet A. 2008;146A:2495–2500.

    Article  Google Scholar 

  3. 3.

    Schaefer GB, Bodensteiner JB. Radiological findings in developmental delay. Semin Pediatr Neurol. 1998;5:33–38.

    CAS  Article  Google Scholar 

  4. 4.

    Achiron R, Achiron A. Development of the human fetal corpus callosum: a high-resolution, cross-sectional sonographic study. Ultrasound Obstet Gynecol. 2001;18:343–347.

    CAS  Article  Google Scholar 

  5. 5.

    Santirocco M, Rodó C, Illescas T, et al. Accuracy of prenatal ultrasound in the diagnosis of corpus callosum anomalies. J Matern Fetal Neonatal Med. 2019. https://doi.org/10.1080/14767058.2019.1609931 [Epub ahead of print].

  6. 6.

    Moutard M-L, Kieffer V, Feingold J, et al. Isolated corpus callosum agenesis: a ten-year follow-up after prenatal diagnosis (how are the children without corpus callosum at 10 years of age?). Prenat Diagn. 2012;32:277–283.

    Article  Google Scholar 

  7. 7.

    Sotiriadis A, Makrydimas G. Neurodevelopment after prenatal diagnosis of isolated agenesis of the corpus callosum: an integrative review. Am J Obstet Gynecol. 2012;206:337.e1–337.e5.

    Article  Google Scholar 

  8. 8.

    des Portes V, Rolland A, Velazquez-Dominguez J, et al. Outcome of isolated agenesis of the corpus callosum: a population-based prospective study. Eur J Paediatr Neurol. 2018;22:82–92.

    Article  Google Scholar 

  9. 9.

    Bedeschi MF, Bonaglia MC, Grasso R, et al. Agenesis of the corpus callosum: clinical and genetic study in 63 young patients. Pediatr Neurol. 2006;34:186–193.

    Article  Google Scholar 

  10. 10.

    Schell-Apacik CC, Wagner K, Bihler M, et al. Agenesis and dysgenesis of the corpus callosum: clinical, genetic and neuroimaging findings in a series of 41 patients. Am J Med Genet A. 2008;146A:2501–2511.

    Article  Google Scholar 

  11. 11.

    Heide S, Keren B, Billette de Villemeur T, et al. Copy number variations found in patients with a corpus callosum abnormality and intellectual disability. J Pediatr. 2017;185:160–.e1.

    Article  Google Scholar 

  12. 12.

    Lord J, McMullan DJ, Eberhardt RY, et al. Prenatal exome sequencing analysis in fetal structural anomalies detected by ultrasonography (PAGE): a cohort study. Lancet. 2019;393:747–757.

    CAS  Article  Google Scholar 

  13. 13.

    Chandler N, Best S, Hayward J, et al. Rapid prenatal diagnosis using targeted exome sequencing: a cohort study to assess feasibility and potential impact on prenatal counseling and pregnancy management. Genet Med. 2018;20:1430–1437.

    Article  Google Scholar 

  14. 14.

    Pangalos C, Hagnefelt B, Lilakos K, Konialis C. First applications of a targeted exome sequencing approach in fetuses with ultrasound abnormalities reveals an important fraction of cases with associated gene defects. PeerJ. 2016;4:e1955.

    Article  Google Scholar 

  15. 15.

    de Koning MA, Haak MC, Adama van Scheltema PN, et al. From diagnostic yield to clinical impact: a pilot study on the implementation of prenatal exome sequencing in routine care. Genet Med. 2019;21:2303–2310.

    Article  Google Scholar 

  16. 16.

    Rasmussen SA, Olney RS, Holmes LB, et al. Guidelines for case classification for the National Birth Defects Prevention Study. Birth Defects Res Part A Clin Mol Teratol. 2003;67:193–201.

    CAS  Article  Google Scholar 

  17. 17.

    Richards S, Aziz N, Bale S, 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;17:405–424.

    Article  Google Scholar 

  18. 18.

    Abou Tayoun A, Mason-Suares H. Considerations for whole exome sequencing unique to prenatal care. Hum Genet. 2019. https://doi.org/10.1007/s00439-019-02085-7 [Epub ahead of print].

  19. 19.

    Malinger G, Zakut H. The corpus callosum: normal fetal development as shown by transvaginal sonography. AJR Am J Roentgenol. 1993;161:1041–1043.

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Solveig Heide MD.

Ethics declarations

Disclosure

The authors declare no conflicts of interest.

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

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Heide, S., Spentchian, M., Valence, S. et al. Prenatal exome sequencing in 65 fetuses with abnormality of the corpus callosum: contribution to further diagnostic delineation. Genet Med (2020). https://doi.org/10.1038/s41436-020-0872-8

Download citation

Keywords

  • exome sequencing
  • anomaly of the corpus callosum
  • agenesis of the corpus callosum
  • prenatal
  • prenatal exome sequencing