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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\u201335% (Williams et al.,\u00a02015). 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\u2010derived 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.<\/jats:p>","DOI":"10.1002\/dvg.23459","type":"journal-article","created":{"date-parts":[[2021,10,29]],"date-time":"2021-10-29T07:47:33Z","timestamp":1635493653000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":39,"title":["Unraveling the complex genetics of neural tube defects: From biological models to human genomics and back"],"prefix":"10.1002","volume":"59","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2982-9448","authenticated-orcid":false,"given":"Paul","family":"Wolujewicz","sequence":"first","affiliation":[{"name":"Center for Neurogenetics Feil Family Brain &amp; 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