A case of Coffin–Siris syndrome with severe congenital heart disease and a novel <i>SMARCA4</i> variant

Abstract

Coffin-Siris syndrome (CSS) is a developmental disability, caused by genomic variants in the gene <i>SMARCA4</i>, in addition to other known genes, but the full spectrum of <i>SMARCA4</i> 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 <i>SMARCA4</i> 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 <i>SMARCA4</i> 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 <i>SMARCA4</i> 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.