5 Common Genes Linked to Congenital Neural Tube Defects – Genetic Education

5 Common Genes Linked to Congenital Neural Tube Defects

Neural tube defects (NTDs) represent a group of congenital anomalies that result from the incomplete closure of the neural tube during embryonic development. There is a proven genetic foundation behind neural tube defects. In this article, we will explore the genetic foundation, various genes and genetic mechanisms behind the development of Neural tube Defects. 

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Disclaimer: The content presented herein has been compiled from reputable, peer-reviewed sources and is presented in an easy-to-understand manner for better comprehension. A comprehensive list of sources is provided after the article for reference.

What are Neural Tube Defects (NTDs)?

During embryonic development, the incomplete closure of the neural tube results in a congenital condition known as Neural Tube Defects (NTDs). The neural tube, a vital structure that forms the precursor to the central nervous system, ideally closes by the end of the fourth week of gestation. 

However, disruption in this closure would result in various congenital malformations and abnormalities affecting the brain, spinal cord, or both, majorly. The severe manifestation results in profound neurological impairment and physical disabilities. While the moderate to mild condition shows some less severe problems.

Along with a definite genetic basis, environmental factors also combine to cause various types of NTDs. folate deficiency, maternal diabetes, certain medications and adverse environmental conditions are also several environmental factors in this case.  

Notedly, a substantial portion of NTD cases has a genetic basis, involving mutations in specific genes or chromosomal abnormalities.

Mechanisms Behind Neural Tube Defects (NTDs):

Neural tube formation is an essential process for developing the central nervous system. And, as aforesaid, is a complex process involving various genes. Various genes involved in this process are SHH, HOX, MTHFR, CBS (Cystathionine beta-synthase), MTR, MTRR and other rare genes. 

Sonic Hedgehog (SHH) has a major role in the development of a neural tube. Simply, it guides cells to form the neural tube. Abruption in this pathway can disrupt the process, preventing the tube from closing correctly and leading to NTDs.

Another set of genes, called Homeobox (HOX) genes, plays a role in giving the neural tube its specific regions. Mutation(s) in these genes increases the likelihood of NTDs. In addition, genes involved in the PCP- planar cell polarity pathway can also cause varied degrees of neural tube defects. 

Adding to this, Abruption in folate metabolism genes (MTHFR) can also result in NTDs. In conclusion, NTDs comprise a complex genetic mechanism and involve various processes. 

Genetic Basis of Neural Tube Defects:

NTDs have a complex genetic basis. The genetic study of NTDs helps us to understand the condition better and also in making various diagnosis and prevention strategies. 

One well-studied gene is MTHFR (methylenetetrahydrofolate reductase), which plays a role in folate metabolism. Mutations in the MTHFR gene are associated with an increased risk of NTDs, impacting the conversion of folate into its active form.

VANGL1 and VANGL2, major genes involved in the planar cell polarity pathway, are essential for proper neural tube closure. Mutations in these genes can lead to abnormalities in tissue patterning during embryonic development, contributing to NTDs.

In addition to this, chromosomal abnormalities, including those involving chromosomes 13, 18, and X, have been linked to neural tube defects. Conditions like trisomy 13 (Patau syndrome) and trisomy 18 (Edwards syndrome) are associated with a higher incidence of NTDs.

Common genes:

  • MTHFR (Methylenetetrahydrofolate reductase)
  • CBS (Cystathionine beta-synthase)
  • MTR (5-methyltetrahydrofolate-homocysteine methyltransferase)
  • MTRR (5-methyltetrahydrofolate-homocysteine methyltransferase reductase)

Rare genes:

  • VANGL1 (Van Gogh-like 1)
  • VANGL2 (Van Gogh-like 2)
  • NODAL (Nodal Homolog)
  • ZIC2 (Zinc finger protein of the cerebellum 2)

5 Important Genes Linked to Neural Tube Defects: 

Gene 1: PAX3 (Paired Box 3)

  • Location: Chromosome 2
  • Function: PAX3 is a transcription factor crucial for neural tube closure during embryonic development.
  • Role in NTDs: PAX3 regulates the expression of genes involved in neural tube closure. Mutations in PAX3 can disrupt this process, leading to incomplete closure and an increased risk of NTDs, including spina bifida and anencephaly.

Gene 2: MTHFR (Methylenetetrahydrofolate Reductase)

  • Location: Chromosome 1
  • Function: MTHFR is involved in folate metabolism, crucial for DNA synthesis and repair.
  • Role in NTDs: MTHFR is essential for converting folate into its active form, vital for DNA synthesis. Mutations in MTHFR can result in impaired folate metabolism, increasing the risk of NTDs due to insufficient folate availability during embryonic development.

Gene 3: ZIC2 (Zinc Finger Protein of the Cerebellum 2)

  • Location: Chromosome 13
  • Function: ZIC2 is a transcription factor involved in the regulation of neural tube development.
  • Role in NTDs: ZIC2 is critical for the transcriptional regulation of genes necessary for neural tube closure. Mutations in ZIC2 can disrupt this regulation, contributing to various forms of NTDs, such as spina bifida and anencephaly.

Gene 4: SHH (Sonic Hedgehog)

  • Location: Chromosome 7
  • Function: SHH is a signaling protein crucial for embryonic development, including neural tube patterning.
  • Role in NTDs: Breakdown in the SHH-governed pathway can cause abnormal neural tube development, affecting proper patterning and growth. This increases the risk of NTDs, including spina bifida and anencephaly.

Gene 5: VANGL1 (Van Gogh-Like 1)

  • Location: Chromosome 1
  • Function: VANGL1 is involved in planar cell polarity, which is crucial for tissue organization during development.
  • Role in NTDs: VANGL1 is essential for coordinating cell movements during neural tube closure. Mutations in VANGL1 can disrupt this coordination, contributing to NTDs, such as spina bifida and anencephaly.

Recent research:

Recent research suggests that somatic mutations of the PCP pathway have been linked with the present condition with a 60% heritability rate. In addition, NTD family history increases the risk of NTD (2).

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In conclusion, These five genes—PAX3, MTHFR, ZIC2, SHH, and VANGL1— have proven and pivotal roles in NTDs. Thus, impacts embryonic development, directly. However, environmental factors also play an important role here. Techniques like microarray and NGS can be utilized for identifying genes and their mutations involved in NTDs.  

To develop targeted interventions and improve outcomes for individuals at risk of neural tube defects, an understanding of gene factors is required.   


  1. Copp AJ, Stanier P, Greene ND. Neural tube defects: recent advances, unsolved questions, and controversies. Lancet Neurol. 2013 Aug;12(8):799-810. doi: 10.1016/S1474-4422(13)70110-8. Epub 2013 Jun 19. PMID: 23790957; PMCID: PMC4023229.
  2. Wolujewicz, Paul, et al. “Unraveling the Complex Genetics of Neural Tube Defects: From Biological Models to Human Genomics and Back.” Genesis, vol. 59, no. 11, 2021, p. e23459, https://doi.org/10.1002/dvg.23459. Accessed 4 Dec. 2023.
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