A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling
A comprehensive molecular study on Coffin-Siris and Nicolaides-Baraitser syndromes identifies a broad molecular and clinical spectrum converging on altered chromatin remodeling
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DOI：
10.1093/hmg/ddt366
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发表时间：
2013-12-20
影响因子：
3.5
通讯作者：
Wollnik, Bernd
中科院分区：
文献类型：
--
作者：
Wieczorek, Dagmar;Boegershausen, Nina;Wollnik, Bernd
已知染色质重塑复合物修饰组蛋白上的化学标记或诱导染色质中的构象变化以调节转录。最近在Coffin-Siris（CSS）和Nicolaides-Baraitser（NCBRS）综合征患者中描述了SWI/SNF染色质重塑复合物不同成员的显性突变。通过对46名CSS和NCBRS患者进行全外显子组测序、基于NGS的23个SWI/SNF复合体基因测序和分子核型分析，我们在2名CSS患者的PHF 6中发现了1个碱基缺失（c.677delG，p.Gly226Glufs*53）和1个错义突变（c.914G>T，p.Cys305Phe）。PHF 6与核小体重塑和脱乙酰化（NuRD）复合物相互作用，暗示第二染色质重塑复合物在CSS样表型发病机制中的功能障碍。总的来说，我们在60%的研究个体（28/46）中发现了位于基因ARID 1A、ARID 1B、SMARCB 1、SMARCE 1、SMARCA 2和PHF 6的突变。我们发现，ARID 1B突变是CSS的主要原因，占已鉴定突变的76%。在初步诊断为NCBRS的个体中也发现了ARID 1B和SMARCB 1突变。这些人显然属于一个小的子集，显示中间CSS/NCBRS表型。我们提出的基因型-表型相关性对于分子筛选策略是重要的。
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>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.