A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling

作者：Wieczorek Dagmar^*; Boegershausen Nina; Beleggia Filippo; Steiner Haldenstaett Sabine; Pohl Esther; Li Yun; Milz Esther; Martin Marcel; Thiele Holger; Altmueller Janine; Alanay Yasemin; Kayserili Hulya; Klein Hitpass Ludger; Bohringer Stefan; Wollstein Andreas; Albrecht Beate; Boduroglu Koray; Caliebe Almuth; Chrzanowska Krystyna; Cogulu Ozgur; Cristofoli Francesca; Czeschik Johanna Christina; Devriendt Koenraad; Dotti Maria Teresa; Elcioglu Nursel; Gener Blanca

来源：Human Molecular Genetics, 2013, 22(25): 5121-5135.

DOI：10.1093/hmg/ddt366

Chromatin remodeling complexes are known to modify chemical marks on histones or to induce conformational changes in the chromatin in order to regulate transcription. Denovodominant mutations in different members of the SWI/SNF chromatin remodeling complex have recently been described in individuals with Coffin-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%26gt;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 ARID1B are the main cause of CSS, accounting for 76% of identified mutations. ARID1B and SMARCB1 mutations were also found in individuals with the initial diagnosis of NCBRS. These individuals apparently belong to a small subset who display an intermediate CSS/NCBRS phenotype. Our proposed genotype-phenotype correlations are important for molecular screening strategies.

• 出版日期2013-12-20
• 单位河北医科大学