Pathogenic Variants Are Definitively Associated with Neural Tube Defects in Humans: New Genotype-Phenotype Correlation and Review of the Literature.

Neural tube defects (NTDs) represent a group of malformations, typically arising from a complex interplay between genetic susceptibility and environmental influences. Increasing evidence points to the contribution of rare pathogenic variants in genes involved in embryonic development in selected cases. To date, two families with NTDs carrying biallelic variants in and have been described. Specifically, germline homozygous pathogenic variants in were identified in three fetuses with anencephaly, thus implicating this gene as a critical regulator of neural tube closure. We describe a family in which five individuals presented with sacral dimples, a subtle midline defect considered a minor malformation. Exome sequencing revealed a heterozygous missense variant, c.487G>A in , segregating with the phenotype. Although sacral dimples are often clinically silent and do not typically cause functional impairment, their presence in multiple relatives highlights a possible shared genetic etiology. Careful phenotypic recognition of such findings can therefore provide valuable insights into underlying molecular mechanisms. This report extends the clinical spectrum of -related anomalies by demonstrating a novel genotype-phenotype correlation. Our findings suggest that variants in this gene may follow a semi-dominant inheritance pattern, with heterozygous carriers manifesting milder phenotypes, such as sacral dimples, while biallelic pathogenic variants lead to severe NTDs. This observation reinforces the association between loss-of-function variants and NTDs and emphasizes the importance of genetic investigations in families where such dysmorphic traits recur. Ultimately, these results contribute to clarifying the molecular basis of NTDs and may inform both genetic counseling and risk stratification in affected families.