Abstract：
Pathogenic variants in SMARCA4 cause Coffin-Siris syndrome (CSS) while those in SMAD6 lead to aortic valve disease and other dysmorphisms. We identified a 6-year-old Thai boy with features of CSS alongside unusual manifestations including, very severe coarctation of the aorta (CoA) requiring coarctectomy in the neonatal period and bilateral radioulnar synostoses. Trio exome sequencing revealed that the patient harbored two de novo variants, a missense c.2475G > T, p.(Trp825Cys) in SMARCA4 and a nonsense c.652C > T, p.(Gln218Ter) in SMAD6. Both of which have never been previously reported. The clinical presentations in our patient are a result of the combinational features of each genetic variant: the SMARCA4 p.(Trp825Cys) variant leads to facial features of Coffin Siris syndrome and Dandy-Walker malformation, while the SMAD6 p.(Gln218Ter) variant underlies radioulnar synostosis. Interestingly, the severity of CoA in the proband is beyond the phenotypic spectra of each genetic variant and may be a result of the synergistic effects of both variants. Here, we report a child with variants in SMARCA4 or SMAD6 with combined features of each plus a severe CoA, possibly due to an additive effect of each variant.
摘要：
SMARCA4的致病变异导致Coffin-Siris综合征（CSS），而SMAD6的致病变异导致主动脉瓣疾病和其他畸形。我们确定了一个6岁的泰国男孩，具有CSS的特征以及不寻常的表现，包括，非常严重的主动脉缩窄（CoA），需要在新生儿期进行缩窄切除术和双侧尺桡骨滑膜。Trio外显子组测序显示患者有两个从头变异，一个错觉c.2475G>T，p.(Trp825Cys)在SMARCA4和无意义的c.652C>T，SMAD6中的p.（Gln218Ter）。这两者以前从未被报道过。我们患者的临床表现是每个遗传变异的组合特征的结果：SMARCA4p。（Trp825Cys）变异导致CoffinSiris综合征和Dandy-Walker畸形的面部特征，而SMAD6p。（Gln218Ter）变体位于尺桡骨滑膜下方。有趣的是,在先证者中CoA的严重程度超出了每个遗传变体的表型谱,并且可能是两种变体的协同作用的结果。这里,我们报告了一个具有SMARCA4或SMAD6变体的儿童，每个变体的特征都加上严重的CoA，可能是由于每个变体的加性效应。
