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Abstract：
The TWIST family is a group of highly conserved basic helix-loop-helix transcription factors. In humans, TWIST1 haploinsufficiency causes Saethre-Chotzen syndrome, which is characterized by craniosynostosis. Heterozygous localized TWIST1 and TWIST2 basic domain substitutions exert antimorphic effects to cause Sweeney-Cox syndrome, Barber-Say syndrome, and ablepharon-macrostomia syndrome, respectively. Sweeney-Cox syndrome, Barber-Say syndrome, and ablepharon-macrostomia syndrome share the facial features of ablepharon, hypertelorism, underdevelopment of the eyelids, and cheek pads adjacent to the corners of the mouth. Existence of phenotypic overlap between Saethre-Chotzen syndrome and Sweeney-Cox syndrome remains unknown. Herein, we document a male infant with the distinctive facial features of ablepharon, hypertelorism, cheek pads adjacent to the corners of the mouth, and bilateral coronal suture craniosynostosis who had a de novo heterozygous mutation in the basic domain of TWIST1, that is, c.351C>G p.Glu117Asp. The pathogenicity of this variant was supported by in silico and in vivo evidence. Our review showed that Sweeney-Cox syndrome appears to share many characteristics with Barber-Say syndrome and ablepharon-macrostomia syndrome except for craniosynostosis, which is a cardinal feature of Saethre-Chotzen syndrome. An amino acid substitution from Glu117 to Asp, both of which are the sole members of negatively charged amino acids, resulted in a prototypic Sweeney-Cox syndrome phenotype. This suggests that any amino acid substitutions at Glu117 would likely lead to the Sweeney-Cox syndrome phenotype or lethality. The present observation suggests that a localized TWIST1 basic domain substitution, that is, p.Glu117Asp, in TWIST1 may exert a mild antimorphic effect similar to that of haploinsufficiency, leading to craniosynostosis and ablepharon.
摘要：
TWIST家族是一组高度保守的碱性螺旋-环-螺旋转录因子。在人类中,TWIST1单倍体功能不全导致Saethre-Chotzen综合征，以颅骨融合为特征。杂合的局部TWIST1和TWIST2基本结构域取代发挥抗畸形作用，导致Sweeney-Cox综合征，Barber-Say综合征,和睑口炎综合征，分别。Sweeney-Cox综合征,Barber-Say综合征,和睑口炎综合征具有睑口炎的面部特征，超端粒,眼睑发育不足，和靠近嘴角的面颊垫。Saethre-Chotzen综合征和Sweeney-Cox综合征之间是否存在表型重叠仍然未知。在这里，我们记录了一个男性婴儿的面部特征，超端粒,靠近嘴角的面颊垫，以及在TWIST1的基本域中具有从头杂合突变的双侧冠状缝合颅骨融合，即，c.351C>Gp.Glu117Asp.该变体的致病性得到了计算机和体内证据的支持。我们的评论显示，除了颅骨融合外，Sweeney-Cox综合征似乎与Barber-Say综合征和睑-巨大口炎综合征具有许多共同特征，这是Saethre-Chotzen综合征的主要特征.从Glu117到Asp的氨基酸置换，两者都是带负电荷的氨基酸的唯一成员，导致原型Sweeney-Cox综合征表型。这表明Glu117处的任何氨基酸取代都可能导致Sweeney-Cox综合征表型或致死性。目前的观察表明，一个局部的TWIST1基本结构域取代，也就是说,p.Glu117Asp,在TWIST1中可能会产生类似于单倍体功能不全的轻度反常作用，导致颅骨融合和上睑。
