Dsouza Nikita R, Zimmermann Michael T, Geddes Gabrielle C
Bioinformatics Research and Development Laboratory, Genomic Sciences and Precision Medicine Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Clinical and Translational Sciences Institute, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Cold Spring Harb Mol Case Stud. 2019 Jun 3;5(3). doi: 10.1101/mcs.a003962. Print 2019 Jun.
Coffin-Siris syndrome (CSS) is a developmental disability, caused by genomic variants in the gene , in addition to other known genes, but the full spectrum of variants that can cause CSS is unknown with 40% of cases not having molecular confirmation. In this report, we identify a patient with CSS, a severe cardiac phenotype, and a novel variant. There is no experimental structure of human SMARCA4, so we use molecular modeling techniques to generate a structural model of human SMARCA4. We then map known variants causative of CSS and our novel variant to the model. We use the resulting information to support the interpretation that the novel variant is causative of disease in our patient. Modeling demonstrates that the variant found in our patient is in a region of SMARCA4 associated with DNA binding, as are the other known pathogenic variants mapped. Because of this structural information, we discuss how these variants may be disease-causing through a dominant negative effect of disrupting DNA binding.
科芬-西里斯综合征（CSS）是一种发育障碍，除其他已知基因外，由该基因中的基因组变异引起，但导致CSS的全部变异谱尚不清楚，40%的病例未得到分子确诊。在本报告中，我们鉴定出一名患有CSS、具有严重心脏表型和一种新型变异的患者。由于没有人类SMARCA4的实验结构，我们使用分子建模技术生成了人类SMARCA4的结构模型。然后，我们将已知的导致CSS的变异和我们的新型变异映射到该模型上。我们利用所得信息支持这样的解释，即新型变异是我们患者疾病的病因。建模表明，我们患者中发现的变异位于SMARCA4中与DNA结合相关的区域，其他已知的致病变异映射到的区域也是如此。基于这一结构信息，我们讨论了这些变异如何通过破坏DNA结合的显性负效应而致病。
