A comprehensive molecular study on coffin-siris and nicolaides-baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling

摘要

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.