Bi-allelic loss of function variants of TBX6 causes a spectrum of malformation of spine and rib including congenital scoliosis and spondylocostal dysostosis

Congenital scoliosis (CS) is a common spinal anomaly and spondylo-costal dysostosis (SCDO) is a rare skeletal dysplasia affecting spine and rib. They have been considered to belong to different disease entities. We examined TBX6 in CS and SCDO and found loss-of-function (LOF) mutations in both. There were two LOF mechanisms: decreased transcriptional activity and mis-localization of the protein. The latter was the main pathogenicity and was confirmed by in vitro model of somitegenesis using iPS cells from a SCDO patient. Bi-allelic LOF of TBX6 causes a spectrum of malformations including CS and SCDO, depending on the severity of LOF. (Drs. Shiro Ikegawa and Nao Otomo,

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