Unraveling the complex genetics of neural tube defects: From biological models to human genomics and back

Abstract

Neural tube defects (NTDs) are a classic example of preventable birth defects for which there is a proven‐effective intervention, folic acid (FA); however, further methods of prevention remain unrealized. In the decades following implementation of FA nutritional fortification programs throughout at least 87 nations, it has become apparent that not all NTDs can be prevented by FA. In the United States, FA fortification only reduced NTD rates by 28–35% (Williams et al., 2015). As such, it is imperative that further work is performed to understand the risk factors associated with NTDs and their underlying mechanisms so that alternative prevention strategies can be developed. However, this is complicated by the sheer number of genes associated with neural tube development, the heterogeneity of observable phenotypes in human cases, the rareness of the disease, and the myriad of environmental factors associated with NTD risk. Given the complex genetic architecture underlying NTD pathology and the way in which that architecture interacts dynamically with environmental factors, further prevention initiatives will undoubtedly require precision medicine strategies that utilize the power of human genomics and modern tools for assessing genetic risk factors. Herein, we review recent advances in genomic strategies for discovering genetic variants associated with these defects, and new ways in which biological models, such as mice and cell culture‐derived organoids, are leveraged to assess mechanistic functionality, the way these variants interact with other genetic or environmental factors, and their ultimate contribution to human NTD risk.

Guideline No. 427: Folic Acid and Multivitamin Supplementation for Prevention of Folic Acid–Sensitive Congenital Anomalies

“…1. Genetic factors include: 3,4,5,12,13 gene polymorphisms that affect the efficiency of folate metabolism; DNA methylation/ epigenetics; and chromosomal anomalies. use of drugs or alcohol.…”

“…In the United States, folic acid fortification has reduced NTD rates by 28%e35%, with a postdfolate food fortification NTD rate of 1 per 2000 live births. 3,4,5 It has been estimated that of the 4%e5% of babies are born with a serious congenital anomaly (malformation, deformation, or disruption), over half (2%e3% of anomalies) can be identified prenatally through sonographic screening. A further 2% of babies have developmental or functional conditions and minor congenital anomalies that are recognized at birth or during their first year of life.…”

“…A further 2% of babies have developmental or functional conditions and minor congenital anomalies that are recognized at birth or during their first year of life. 3,4,5…”

Systems biology analysis of human genomes points to key pathways conferring spina bifida risk

“…Toward functional testing of SB genetic contributions, the hypotheses generated using systems biology-based computational strategies will require biological validation, likely utilizing genome editing of individual genes and regulatory sequences, singly and in combination, in the mouse in vivo and human stem cell systems (reviewed in ref. 67). These animal and human models offer additional opportunities to test environmental stressors that mimic toxic exposures and intrauterine conditions that undoubtedly interact with the genome and impact the epigenome to tip the epistatic load toward SB (20).…”

Identification of immune-related biomarkers in embryos with neural tube defects via a bioinformatics analysis

“…Karzbrun et al found that the width of the nerve tissue determines the shape of the neural tube, and used a chip-based culture system to reconstruct a neural tube in a petri dish that was about 90% similar to that of humans ( 7 ). Wolujewicz et al showed that genetic variation in the genome is an important factor affecting in NTDs ( 8 ). Despite the strengthening of FA treatments in the last 20 years, the incidence of NTDs remains unacceptably high.…”