Caengprasath Natarin, Buasong Aayalida, Ittiwut Chupong, Khongphatthanayothin Apichai, Porntaveetus Thantrira, Shotelersuk Vorasuk
Center of Excellence for Medical Genomics, Department of Pediatrics, Faculty of Medicine, Chulalongkorn University, Bangkok, Thailand; Excellence Center for Medical Genetics, King Chulalongkorn Memorial Hospital, The Thai Red Cross Society, Bangkok, Thailand.
Center of Excellence in Arrhythmia Research, Department of Medicine, Chulalongkorn University and Bangkok General Hospital, Bangkok, Thailand.
Eur J Med Genet. 2022 Nov;65(11):104601. doi: 10.1016/j.ejmg.2022.104601. Epub 2022 Aug 29.
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.
SMARCA4基因的致病性变异会导致科芬-西里斯综合征（CSS），而SMAD6基因的致病性变异则会引发主动脉瓣疾病和其他畸形。我们鉴定出一名6岁的泰国男孩，他具有CSS的特征，同时还有一些不寻常的表现，包括非常严重的主动脉缩窄（CoA），在新生儿期需要进行缩窄切除术，以及双侧桡尺骨融合。三联体外显子组测序显示，该患者携带两个新生变异，一个是SMARCA4基因的错义变异c.2475G>T，p.(Trp825Cys)，另一个是SMAD6基因的无义变异c.652C>T，p.(Gln218Ter)。此前这两个变异均未见报道。我们患者的临床表现是每个基因变异综合特征的结果：SMARCA4基因的p.(Trp825Cys)变异导致科芬-西里斯综合征的面部特征和丹迪-沃克畸形，而SMAD6基因的p.(Gln218Ter)变异是桡尺骨融合的基础。有趣的是，先证者CoA的严重程度超出了每个基因变异的表型范围，可能是两个变异协同作用的结果。在此，我们报告一名患有SMARCA4或SMAD6基因变异的儿童，其具有每个变异的综合特征以及严重的CoA，这可能是由于每个变异的累加效应所致。
