Spina bifida has a genetic component, but it is not caused by a single gene. It arises from a complex interaction of multiple genetic and environmental factors, making it what researchers call a multifactorial condition. Most cases are sporadic, meaning they occur in families with no prior history of the disorder. A small percentage of cases do run in families, but spina bifida does not follow a clear or predictable inheritance pattern.
How Genetics Contribute to Spina Bifida
No single gene causes spina bifida on its own. Instead, variations in several genes can each raise the risk slightly, and when multiple variants combine with certain environmental conditions during pregnancy, the neural tube may fail to close properly during the first month of development. This is why two parents who are perfectly healthy can have a child with spina bifida, and why a parent with spina bifida will most likely have unaffected children.
The strongest genetic candidate involves a gene called MTHFR, which produces an enzyme the body needs to process folate (a B vitamin critical for early fetal development). A common variant of this gene, known as C677T, reduces the enzyme’s activity by more than 50% in people who inherit two copies. Carrying two copies of this variant roughly doubles the risk of neural tube defects (odds ratio 2.56), while carrying just one copy raises it by about 50% (odds ratio 1.52). In Ireland, where this variant is relatively common, it accounts for approximately 26% of neural tube defect cases.
Researchers have also identified mutations in genes involved in a signaling pathway that helps cells organize during early development. Mutations in genes called VANGL1 and VANGL2 have been found in patients with spina bifida, though they appear to contribute to a small fraction of cases, roughly 2.5% of certain closed spinal defects. These genes are essential for the physical process of neural tube closure, and defects in them disrupt the coordinated cell movements required to seal the tube shut.
Family Recurrence Risk
If one child in a family is born with spina bifida, the recurrence risk for a subsequent pregnancy is 2% to 5%. That is significantly higher than the general population rate of about 1 in 2,875 births (roughly 0.035%), but it still means the vast majority of siblings will be unaffected. First-degree relatives of someone with spina bifida, including siblings and children, carry a higher risk than the general population, which confirms that shared genetics play a role even though no single gene is responsible.
These recurrence figures hold for both open and closed forms of the condition. One study found a 4.12% recurrence rate for any type of neural tube defect in families where the first affected child had a closed spinal defect.
Chromosomal Conditions That Increase Risk
In some cases, spina bifida occurs alongside a chromosomal abnormality rather than as an isolated condition. Trisomy 18 (Edwards syndrome), trisomy 13 (Patau syndrome), and trisomy 21 (Down syndrome) have all been associated with neural tube defects. Other rarer chromosomal conditions, including trisomy 9, monosomy X (Turner syndrome), and various mosaic trisomies, have also been linked. When spina bifida appears with a chromosomal abnormality, the genetic cause is more straightforward, but these cases represent a minority of all spina bifida diagnoses.
Why Folic Acid Matters So Much
The reason folic acid supplementation before and during early pregnancy is so strongly recommended is that it can compensate for many of the genetic vulnerabilities that raise spina bifida risk. Folate fuels several essential processes during neural tube formation: it helps cells divide, supports DNA construction, and generates a key molecule the body uses to regulate gene activity. When a developing embryo has genetic variants that slow folate processing, adequate maternal folate intake can often bridge the gap.
Animal studies illustrate this interaction clearly. Mice with mutations in developmental signaling genes developed neural tube defects at high rates on a normal diet, but moderate folic acid supplementation dramatically reduced those defects. The same pattern holds in humans. The MTHFR C677T variant, for example, does not always raise spina bifida risk on its own. In one study, the variant only significantly increased risk when combined with other genetic factors or low folate status. This is why population-wide folic acid fortification of grain products, adopted in the U.S. in 1998, has been effective: it helps protect the pregnancies most genetically vulnerable without needing to identify those pregnancies in advance.
Environmental Factors That Add to Genetic Risk
Several maternal health conditions interact with genetic predisposition to further raise the odds. Pre-gestational diabetes is one of the most significant. Mothers with diabetes and lower folic acid intake had nearly four times the odds of having a child with spina bifida compared to mothers without either factor. When those same mothers had higher folic acid intake, the risk dropped substantially, suggesting that folate can partially offset the diabetes-related risk.
Maternal obesity also raises the likelihood of spina bifida independently. In one large study, 19% of mothers whose babies had spina bifida were obese, compared to about 11% of control mothers. Unlike diabetes, higher folic acid intake did not meaningfully reduce the obesity-associated risk, hinting that obesity may influence neural tube development through mechanisms beyond folate metabolism.
Certain antiseizure medications taken during the first trimester also increase risk. Valproate exposure raises the prevalence of spina bifida to 1 to 2% of exposed pregnancies, with one prospective study finding rates as high as 5.4%. Carbamazepine carries a lower but still elevated risk of about 0.5%. These medications can interfere with folate metabolism or directly affect fetal development, compounding any underlying genetic susceptibility.
Prevalence Varies by Ethnicity
Spina bifida rates differ across racial and ethnic groups in the United States, further supporting a genetic component. Hispanic populations have the highest rate at 3.80 per 10,000 live births, followed by non-Hispanic white populations at 3.09 per 10,000 and non-Hispanic Black populations at 2.73 per 10,000. These differences likely reflect a combination of genetic variation in folate-processing genes, dietary patterns, and access to prenatal vitamins, though the relative contribution of each factor is difficult to separate.
Prenatal Detection
Because spina bifida involves both genetic and environmental causes and no single genetic test can predict it, screening relies on other methods. A blood test measuring a protein called alpha-fetoprotein (AFP) is typically performed between 15 and 20 weeks of pregnancy, with 16 to 18 weeks being the recommended window. This test detects 65% to 80% of open spina bifida cases. Ultrasound imaging, often performed around the same time, provides additional diagnostic detail and can identify the specific location and severity of the defect.
These screening tools detect spina bifida after it has already formed rather than predicting genetic risk beforehand. There is currently no genetic test that can reliably predict whether an individual pregnancy will result in spina bifida, precisely because the condition depends on the combined effects of many small genetic contributions and the uterine environment during a narrow window of early development.