Exome sequencing unravels unexpected differential diagnoses in individuals with the tentative diagnosis of Coffin-Siris and Nicolaides-Baraitser syndromes
Exome sequencing unravels unexpected differential diagnoses in individuals with the tentative diagnosis of Coffin-Siris and Nicolaides-Baraitser syndromes
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DOI：
10.1007/s00439-015-1535-8
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发表时间：
2015-06-01
期刊：
影响因子：
5.3
通讯作者：
Wieczorek, Dagmar
中科院分区：
文献类型：
--
作者：
Bramswig, Nuria C.;Luedecke, Hermann-Josef;Wieczorek, Dagmar
Coffin-Siris综合征（CSS）和Nicolaides-Baraitser综合征（NCBRS）是罕见的智力残疾/先天性畸形综合征，代表不同的实体，但显示出相当大的临床重叠。它们是由编码BRG 1和BRM相关因子（BAF）复合物成员的基因突变引起的。然而，有许多临床诊断为CSS或NCBRS的患者的致病突变尚未确定。在这项研究中，我们在10个先前描述但未解决的CSS或NCBRS初步诊断的个体中进行了基于trio的全外显子组测序（WES），并在10个个体中的9个中发现了致病突变。有趣的是，我们的WES分析揭示了重叠的鉴别诊断，包括Wiedemann-Steiner，Kabuki和Adams-Oliver综合征。此外，在GRIN 2A和SHANK 3中鉴定了最可能的致病性从头突变。此外，基于trio的WES检测到SMARCA 2和SMARCA 4缺失，这在先前的Haloplex靶富集和已知CSS/NCBRS基因的下一代测序中没有注释，强调了WES作为诊断工具的优势。总之，我们讨论了临床遗传学中的表型和诊断挑战，建立了重要的鉴别诊断，并强调了BAF复杂性疾病和表观遗传背景突变引起的其他疾病的主要特征和广泛的临床谱。
Coffin-Siris syndrome (CSS) and Nicolaides-Baraitser syndrome (NCBRS) are rare intellectual disability/congenital malformation syndromes that represent distinct entities but show considerable clinical overlap. They are caused by mutations in genes encoding members of the BRG1- and BRM-associated factor (BAF) complex. However, there are a number of patients with the clinical diagnosis of CSS or NCBRS in whom the causative mutation has not been identified. In this study, we performed trio-based whole-exome sequencing (WES) in ten previously described but unsolved individuals with the tentative diagnosis of CSS or NCBRS and found causative mutations in nine out of ten individuals. Interestingly, our WES analysis disclosed overlapping differential diagnoses including Wiedemann-Steiner, Kabuki, and Adams-Oliver syndromes. In addition, most likely causative de novo mutations were identified in GRIN2A and SHANK3. Moreover, trio-based WES detected SMARCA2 and SMARCA4 deletions, which had not been annotated in a previous Haloplex target enrichment and next-generation sequencing of known CSS/NCBRS genes emphasizing the advantages of WES as a diagnostic tool. In summary, we discuss the phenotypic and diagnostic challenges in clinical genetics, establish important differential diagnoses, and emphasize the cardinal features and the broad clinical spectrum of BAF complex disorders and other disorders caused by mutations in epigenetic landscapers.