PROJECT SUMMARY Birth defects impact every organ system with the most common being congenital heart defects closely followed by neural tube defects (NTDs). NTDs are defined as the group of birth defects that impact either the brain or spine and are caused by the improper closure of the embryonic neural tube. The commonest types of NTDs are spina bifida, encephalocele, and anencephaly.5 Globally, about 300,000 to 400,000 babies are born with NTDs resulting in 88,000 deaths and 8.6 million disability adjusted life years (DALYs) annually with 94% of severe cases occurring in LMICs. In LMICs, over 1.67/1000 babies born annually have NTDs, and of these 1.13/1000 have spina bifida, 0.25/1000 have anencephaly, and 0.15/1000 have encephalocele. Despite the importance of NTDs, 61.9% (120/194) of the World Health Organization (WHO) member countries lack data on NTDs and therefore the reported figures of NTDs may even be higher. In Africa, where most of the Sub-Saharan countries are LMICs, the prevalence of NTDs is reported to be 1.2/1000 live births and of these 0.49/1000 have spina bifida, 0.23/1000 have anencephaly, and 0.17/1000 have encephalocele. In Uganda, the burden of NTDs has continued to be a serious public health challenge, though there is limited updated data. There are several risk factors that have been postulated to lead to the increased prevalence of NTDs though the definitive cause is still unknown. A combination of various factors has been reported that may involve environmental-gene interactions during neural tube development. To date, there is a paucity of information about the role of the reported risk factors and the mutations or alterations in morphology or functions of specific genes, receptors, and enzymes responsible for folic acid metabolism in African NTD samples. Therefore, the main objective of the current study is to determine the association between relevant risk factors and NTDs and their influence on the reported genes and receptors. Our primary study design is a prospective case-control study. We will recruit 98 NTD newborns and their mothers along with our matched control of 98 newborns and their mothers without NTDs from the cross sectional sample detailed above. We will assess demographic, socioeconomic, family history, infectious exposures, medications, herbal use, environmental chemical exposure, nutritional deficiencies, and food consumption patterns using a structured questionnaire. We will also take blood samples from newborns and their mothers to determine the blood levels of aflatoxins, fumonisins, and ochratoxins; blood levels of folic acid and active 5-MTHF metabolite; and genetic variation in hFRa, MTHFR, and CELSR genes. Findings from our study will help inform NTDs management practices and policies in Uganda and set the stage for future NTDs prevention and intervention studies.