A case of Coffin-Siris syndrome with severe congenital heart disease and a novel SMARCA4 variant. Cold Spring Harb Mol Case Stud 2019 Jun;5(3)
Date
06/05/2019Pubmed ID
31160358Pubmed Central ID
PMC6549553DOI
10.1101/mcs.a003962Scopus ID
2-s2.0-85067212433 (requires institutional sign-in at Scopus site) 9 CitationsAbstract
Coffin-Siris syndrome (CSS) is a developmental disability, caused by genomic variants in the gene SMARCA4, in addition to other known genes, but the full spectrum of SMARCA4 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 SMARCA4 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 SMARCA4 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 SMARCA4 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.
Author List
Dsouza NR, Zimmermann MT, Geddes GCAuthor
Michael T. Zimmermann PhD Director, Assistant Professor in the Clinical and Translational Science Institute department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Abnormalities, MultipleDNA Helicases
Face
Hand Deformities, Congenital
Heart Diseases
Humans
Infant, Newborn
Intellectual Disability
Male
Micrognathism
Models, Molecular
Mutation
Neck
Nuclear Proteins
Transcription Factors
