Coffin-Siris Syndrome and the BAF Complex: Genotype-Phenotype Study in 63 Patients
- 8 August 2013
- journal article
- research article
- Published by Hindawi Limited in Human Mutation
- Vol. 34 (11), 1519-1528
- https://doi.org/10.1002/humu.22394
Abstract
De novo germline variants in several components of the SWI/SNF‐like BAF complex can cause Coffin–Siris syndrome (CSS), Nicolaides–Baraitser syndrome (NCBRS), and nonsyndromic intellectual disability. We screened 63 patients with a clinical diagnosis of CSS for these genes (ARID1A, ARID1B, SMARCA2, SMARCA4, SMARCB1, and SMARCE1) and identified pathogenic variants in 45 (71%) patients. We found a high proportion of variants in ARID1B (68%). All four pathogenic variants in ARID1A appeared to be mosaic. By using all variants from the Exome Variant Server as test data, we were able to classify variants in ARID1A, ARID1B, and SMARCB1 reliably as being pathogenic or nonpathogenic. For SMARCA2, SMARCA4, and SMARCE1 several variants in the EVS remained unclassified, underlining the importance of parental testing. We have entered all variant and clinical information in LOVD‐powered databases to facilitate further genotype–phenotype correlations, as these will become increasingly important because of the uptake of targeted and untargeted next generation sequencing in diagnostics. The emerging phenotype–genotype correlation is that SMARCB1 patients have the most marked physical phenotype and severe cognitive and growth delay. The variability in phenotype seems most marked in ARID1A and ARID1B patients. Distal limbs anomalies are most marked in ARID1A patients and least in SMARCB1 patients. Numbers are small however, and larger series are needed to confirm this correlation.This publication has 35 references indexed in Scilit:
- Novel mutations target distinct subgroups of medulloblastomaNature, 2012
- The landscape of cancer genes and mutational processes in breast cancerNature, 2012
- Haploinsufficiency of ARID1B, a Member of the SWI/SNF-A Chromatin-Remodeling Complex, Is a Frequent Cause of Intellectual DisabilityAmerican Journal of Human Genetics, 2012
- Next-generation sequencing demands next-generation phenotypingHuman Mutation, 2012
- Corpus callosum abnormalities, intellectual disability, speech impairment, and autism in patients with haploinsufficiency of ARID1BClinical Genetics, 2011
- ATP-dependent chromatin remodeling: genetics, genomics and mechanismsCell Research, 2011
- ARID1AMutations in Endometriosis-Associated Ovarian CarcinomasThe New England Journal of Medicine, 2010
- Mammalian SWI/SNF-A Subunit BAF250/ARID1 Is an E3 Ubiquitin Ligase That Targets Histone H2BMolecular and Cellular Biology, 2010
- Germline Nonsense Mutation and Somatic Inactivation of SMARCA4/BRG1 in a Family with Rhabdoid Tumor Predisposition SyndromeAmerican Journal of Human Genetics, 2010
- ES cell pluripotency and germ-layer formation require the SWI/SNF chromatin remodeling component BAF250aProceedings of the National Academy of Sciences of the United States of America, 2008