Smad6, an intracellular inhibitor of the bone morphogenetic protein (BMP) signalling pathway, is crucial for various biological processes. It plays a role in the transition from active blood vessel network expansion to vascular homeostasis in endothelial cells, and also impacts granulosa cell proliferation and follicle growth rate in cattle [5,8].

SMAD6-deficiency has been associated with three distinct human congenital conditions: congenital heart diseases (left ventricular obstruction and conotruncal defects), craniosynostosis, and radioulnar synostosis. Heterozygous loss-of-function variants in SMAD6 increase the risk of these disorders, with no clear genotype-phenotype correlation. Even identical nucleotide changes can lead to different phenotypes. In craniosynostosis, SMAD6 mutations are associated with neuropsychiatric development issues, and both nonsyndromic and syndromic presentations of the disease, especially metopic synostosis. Homozygous SMAD6 variants expand the phenotypic spectrum to include craniosynostosis and radioulnar synostosis [1,2,3,4]. In nonsyndromic radioulnar synostosis, SMAD6 is frequently mutated, mostly with loss-of-function variants [6]. Some pathogenic SMAD6 variants can activate the BMP signaling pathway through deamidation [7].

In conclusion, Smad6 is essential in regulating the BMP signalling pathway. Its deficiency is linked to multiple congenital disorders in humans. Studies on SMAD6-related mouse models and human genetic variants have provided insights into the role of Smad6 in these disease conditions, highlighting its significance in understanding the pathogenesis and potentially developing new therapeutic strategies for these congenital diseases [1].