Novel TBX1 loss-of-function mutation causes isolated conotruncal heart defects in Chinese patients without 22q11.2 deletion.

[22q11.2 deletion syndrome]

TBX 1 and CRKL haploinsufficiency is thought to cause the cardiac phenotype of the 22 q 11 .2 deletion syndrome . However , few unequivocal mutations of TBX 1 and CRKL have been discovered in isolated conotrucal heart defects (CTDs ) patients . The aim of the study was to screen the mutation of TBX 1 and CRKL in isolated CTDs Chinese patients without 22 q 11 .2 deletion and identify the pathomechanism of the missense mutations .We enrolled 199 non-22 q 11 .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 .Screening of the TBX 1 coding sequence identified a de novo missense mutation (c .385 G → A ; p .E 129 K ) and a known polymorphism (c .928 G → A ; p .G 310 S ). In vitro experiments demonstrate that the TBX 1 E 129 K variant almost lost transactivation activity . The TBX 1 G 310 S variant seems to affect the interaction of TBX 1 with other factors . Computer molecular dynamics simulations showed the de novo missense mutation is likely to affect TBX 1 -DNA interaction . No mutation of CRKL gene was found .These observations suggest that the TBX 1 loss -of-function mutation may be involved in the pathogenesis of isolated CTDs . This is the first human missense mutation showing that TBX 1 is a candidate causing isolated CTDs in Chinese patients without 22 q 11 .2 deletion .