Bi-allelic loss of function variants ofTBX6causes a spectrum of malformation of spine and rib including congenital scoliosis and spondylocostal dysostosis

Abstract

BackgroundCongenital scoliosis (CS) is a common vertebral malformation. Spondylocostal dysostosis (SCD) is a rare skeletal dysplasia characterised by multiple vertebral malformations and rib anomalies. In a previous study, a compound heterozygosity for a null mutation and a risk haplotype composed by three single-nucleotide polymorphisms in TBX6 have been reported as a disease-causing model of CS. Another study identified bi-allelic missense variants in a SCD patient. The purpose of our study is to identify TBX6 variants in CS and SCD and examine their pathogenicity.MethodsWe recruited 200 patients with CS or SCD and investigated TBX6 variants. We evaluated the pathogenicity of the variants by in silico prediction and in vitro experiments.ResultsWe identified five 16p11.2 deletions, one splice-site variant and five missense variants in 10 patients. In vitro functional assays for missense variants identified in the previous and present studies demonstrated that most of the variants caused abnormal localisation of TBX6 proteins. We confirmed mislocalisation of TBX6 proteins in presomitic mesoderm cells induced from SCD patient-derived iPS cells. In induced cells, we found decreased mRNA expressions of TBX6 and its downstream genes were involved in somite formation. All CS patients with missense variants had the risk haplotype in the opposite allele, while a SCD patient with bi-allelic missense variants did not have the haplotype.ConclusionsOur study suggests that bi-allelic loss of function variants of TBX6 cause a spectrum of phenotypes including CS and SCD, depending on the severity of the loss of TBX6 function.

Altered Cogs of the Clock: Insights into the Embryonic Etiology of Spondylocostal Dysostosis

“…Rib anomalies were similar to those in SCDO type 1 and 2 [14,15]. An additional report was made of an individual carrying two distinct mutations in LFNG, with multiple vertebral defects along the entire spine [16,17]. In both reported cases, the identified missense mutations were found to impair Lfng enzymatic activity and/or subcellular localization [17].…”

“…The affected individuals, all male, had a mixture of hemivertebrae and blocks of fused vertebral segments, moderate scoliosis affecting the middle thoracic region, with little involvement of the ribs [22,23]. Multiple other cases have also been reported and the underlying TBX6 mutations include 16p11.2 genomic deletions, as well as nonsense and frameshift mutations, some of which were found to alter TBX6 subcellular localization and/or transcriptional activity [16,24,25];…”

TBX6 missense variants expand the mutational spectrum in a non‐Mendelian inheritance disease

“…The remaining four variants all showed a LoF by mislocalization of mutant TBX6 proteins. That study suggests that bi‐allelic LoF mutations of TBX6 would cause a spectrum of phenotype including CS and SCD according to the severity of the loss of TBX6 function during somitogenesis (Otomo et al, ).…”

Identification of novel FBN1 variations implicated in congenital scoliosis

“…We are grateful to the patients, their families, clinical surgeons, and genetic counselors for providing samples and clinical histories. This research was supported in part by the National Natural Deciphering Disorders Involving Scoliosis and COmorbidities (DISCO) study Guixing Qiu 1,4,9 , Zhihong Wu 4,8,9 , Jianguo Zhang 1,4,9 , Nan Wu 1,4,9 , Shengru Wang 1 , Jiaqi Liu 4,5 , Sen Liu 1,4 , Yuzhi Zuo 1 , Gang Liu 1,4 , Yuanqiang Zhang 1,2 , Chenxi Yu 1,2 , Sen Zhao 1,4 , Lianlei Wang 1,2 , Yanxue Zhao 1 , Zihui Yan 1,2 , Xinzhuang Yang 8 , Hengqiang Zhao 10 , Yuchen Niu 8 , Mao Lin 1,2,3 , Jiachen Lin 1 .…”

“…We subsequently recapitulated this compound heterozygosity model in a gene-edited mouse [7], and defined the unique and clinically actionable phenotype of a monogenic form of CS, TBX6-associated CS (TACS) [8]. However, this model can explain only about 10% of CS [8,9]. Many other contributor genes remain to be elucidated.…”