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Background  TBX1 and CRKL haploinsufficiency is thought to cause the cardiac phenotype of the 22q11.2 deletion syndrome. However, few unequivocal mutations of  TBX1  and  CRKL  have been discovered in isolated conotrucal heart defects (CTDs) patients. The aim of the study was to screen the mutation of  TBX1  and  CRKL  in isolated CTDs Chinese patients without 22q11.2 deletion and identify the pathomechanism of the missense mutations.    Methods  We enrolled 199 non-22q11.2 deletion patients with CTDs and 139 unrelated healthy controls. Gene sequencing were performed for all of them. The functional data of mutations were obtained by  in vitro  transfection and luciferase experiments and computer modelling.    Results  Screening of the  TBX1  coding sequence identified a  de novo  missense mutation (c.385G → A; p.E129K) and a known polymorphism (c.928G → A; p.G310S). In vitro experiments demonstrate that the TBX1 E129K  variant almost lost transactivation activity. The TBX1 G310S  variant seems to affect the interaction of TBX1 with other factors. Computer molecular dynamics simulations showed the  de novo  missense mutation is likely to affect TBX1-DNA interaction. No mutation of  CRKL  gene was found.    Conclusions  These observations suggest that the TBX1 loss-of-function mutation may be involved in the pathogenesis of isolated CTDs. This is the first human missense mutation showing that TBX1 is a candidate causing isolated CTDs in Chinese patients without 22q11.2 deletion.

Novel TBX1loss-of-function mutation causes isolated conotruncal heart defects in Chinese patients without 22q11.2 deletion