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Exome analysis in an Estonian multiplex family with neural tube defects—a case report

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Abstract

Introduction

Neural tube defects (NTDs) are a group of common and severe congenital birth defects that occur during early embryonic development due to incomplete closure of the neural tube. The genetic architecture of human NTDs, including spina bifida and hydrocephalus, is highly heterogeneous, with multiple genes/loci and both gene-gene and gene-environment interactions involved. Hence, the variation in outcomes also most likely relates to a combination of the severity of different variants in multiple genes and genetic modifiers affecting the biochemical traits.

Methods

Here, we present a multiple-spouse family with one pedigree lineage where three brothers are affected with NTDs—two lumbar spina bifidas without hydrocephalus and one obstructive hydrocephalus. We sequenced the exomes of three NTD patients and their parents.

Results

The analysis revealed a heterozygous c.844ins68 variant in CBS, which was carried by all affected individuals and inherited from their mother. All affected individuals had a variable set of additional low frequency deleterious variants in PTK7, PLCD4, IL4I1 or RASSF4 as likely causal loci contributing to the disease development.

Conclusion

This report extends the current knowledge of the genetic background of NTDs and proposes that common and low frequency variants in genes involved mostly in one-carbon metabolism or planar cell polarity (PCP) pathways can act in an additive manner to increase the genetic risk of the disease.

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Acknowledgments

We would like to acknowledge High Performance Computing Center of University of Tartu. This study was funded by EU H2020 grants 692145, 676550, 654248, the Estonian Research Council Grant IUT20-60 and European Union through the European Regional Development Fund (Project No. 2014-2020.4.01.15-0012 GENTRANSMED).

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Authors and Affiliations

  1. Estonian Genome Center, University of Tartu, Riia 23b, 51010, Tartu, Estonia

    Liina Pappa, Mart Kals, Paula Ann Kivistik, Andres Metspalu & Tiit Nikopensius

  2. Tallinn Children’s Hospital, Tallinn, Estonia

    Ann Paal

Authors
  1. Liina Pappa
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  2. Mart Kals
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  3. Paula Ann Kivistik
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  4. Andres Metspalu
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Corresponding author

Correspondence to Liina Pappa.

Ethics declarations

Ethical approval for the study was obtained from the Ethics Review Committee on Human Research of the University of Tartu. All participants signed an informed consent form prior to enrolment in this study. For minors, consent was obtained from their parents.

Conflict of interest

The authors of this article have no conflict of interest to declare.

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Pappa, L., Kals, M., Kivistik, P.A. et al. Exome analysis in an Estonian multiplex family with neural tube defects—a case report. Childs Nerv Syst 33, 1575–1581 (2017). https://doi.org/10.1007/s00381-017-3491-1

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  • DOI: https://doi.org/10.1007/s00381-017-3491-1

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