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Background: Rare mutations in multiple genes have been associated with human neural tube defects (NTDs), but their causative roles in NTDs disease are poorly understood. Insufficiency of the ribosomal biogenesis gene treacle ribosome biogenesis factor 1(Tcof1) results in cranial NTDs and craniofacial malformations in mice. Here, we aimed to identify genetic association of TCOF1 with human NTDs. Methods: High‐throughput sequencing targeted on TCOF1 was performed on samples from 355 human cases affected by NTDs and 225 controls from a Han Chinese population. Results: Four novel missense variants were found in the NTD cohort. Cell‐based assays indicated that the p.(A491G) variant carried by an individual, who shows anencephaly and single‐nostril abnormality, attenuates production of total proteins, suggesting a loss‐of‐function mutation in ribosomal biogenesis. Importantly, this variant promotes nucleolar disruption and stabilizes p53 protein, highlighting an unbalancing effect on cell apoptosis. Conclusions: This study explored the functional impact of a missense variant in TCOF1, implicating a set of novel causative biological factors involved in the pathogenicity of human NTDs, particularly whom combined with craniofacial abnormality. [ABSTRACT FROM AUTHOR]

Congenital malformations, such as neural tube defects (NTDs) and congenital heart disease (CHD), cause significant fetal mortality and childhood morbidity. NTDs are a common congenital anomaly, and are typically induced by higher maternal homocysteine (Hcy) levels and abnormal folate metabolism. The gene encoding methionine synthase reductase ( MTRR) is essential for adequate remethylation of Hcy. Previous studies have focused on the coding region of genes involved in one-carbon metabolism, but recent research demonstrates that an allelic change in a non-coding region of MTRR ( rs326119) increases the risk of CHD. We hypothesized that this variant might contribute to the etiology of NTDs as well, based on a common role during early embryogenesis. In the present study, 244 neural tube defect cases and 407 controls from northern China were analyzed to determine any association (by χ test) between rs326119 and disease phenotypes. Significant increased risk of anencephaly was seen in MTRR variant rs326119 heterozygote (het) and homozygote (hom) individuals [odds ratios (OR) = 1.81; OR = 2.05)]. Furthermore, this variant was also a risk factor for congenital malformations of the adrenal gland (OR = 1.85), likely due to multiple systemic malformations in the NTDs case population. Our present data indicate that the rs326119 non-coding variant of MTRR has a pleiotropic effect on the development of multiple tissues, especially during early stages in utero. This suggests the allelic state of MTRR is a significant clinical factor affecting Hcy levels and optimal folic supplementation. [ABSTRACT FROM AUTHOR]