Akademik Veri Yönetim Sistemi
Human Molecular Genetics, cilt.22, sa.25, ss.5121-5135, 2013 (SCI-Expanded)
Chromatin remodeling complexes areknowntomodify chemical marks on histones or to induce conformational changes in the chromatin in order to regulate transcription. Denovodominant mutations in differentmembers of theSWI/SNFchromatin remodelingcomplexhaverecentlybeendescribed in individuals withCoffin-Siris(CSS) and Nicolaides-Baraitser (NCBRS) syndromes. Using a combination of whole-exome sequencing, NGS-based sequencing of 23 SWI/SNF complex genes, and molecular karyotyping in 46 previously undescribed individuals with CSS and NCBRS, we identified a de novo 1-bp deletion (c.677delG, p.Gly226Glufs*53) and a de novo missense mutation (c.914G>T, p.Cys305Phe) in PHF6 in two individuals diagnosed with CSS. PHF6 interacts with the nucleosome remodeling and deacetylation (NuRD) complex implicating dysfunction of a second chromatin remodeling complex in the pathogenesis of CSS-like phenotypes. Altogether, we identified mutations in 60% of the studied individuals (28/46), located in the genes ARID1A, ARID1B, SMARCB1, SMARCE1, SMARCA2, and PHF6.We show that mutations in ARID1Bare the main cause of CSS, accounting for76%of identified mutations. ARID1B andSMARCB1mutations were also found in individuals with the initial diagnosis ofNCBRS. These individuals apparently belong to a small subset who display an intermediateCSS/NCBRS phenotype. Our proposed genotype-phenotype correlations are important for molecular screening strategies. © The Author 2013.