BRG1/BRM相关因子(BAF)复合物是一种染色质重塑复合物,在基因调控中起着至关重要的作用。编码BAF亚基的基因缺陷导致BAFopathies,一组具有广泛基因座和表型异质性的神经发育障碍。
我们回顾性分析了16,243例临床外显子组测序(ES)患者的数据,重点是BAF复合物。我们应用了基因型优先的方法,结合预测的基因约束提出候选BAFopathy基因。
我们确定了127例携带致病变异的患者,可能的致病变异,或11种已知BAFopathy基因中临床意义未知的从头变异。其中包括34例使用ES重新分析进行分子诊断的患者,这些患者具有新的基因疾病证据(n=21)或已知BAFopathy基因的变异重新分类(n=13)。我们还在4个候选BAFopathy基因中鉴定了从头或预测的功能丧失变异,包括ACTL6A,BICRA(在本研究中涉及Coffin-Siris综合征),PBRM1和SMARCC1。
我们报告了ES队列中BAFO病的突变谱。对ES数据的基因型驱动和基于途径的重新分析确定了与BAFopathies有关的候选基因的新证据。需要对其他患者进行进一步的机械和表型表征,以确认其在人类疾病中的作用并描绘其相关的表型谱。
BRG1/BRM-associated factor (BAF) complex is a chromatin remodeling complex that plays a critical role in gene regulation. Defects in the genes encoding BAF subunits lead to BAFopathies, a group of neurodevelopmental disorders with extensive locus and phenotypic heterogeneity.
We retrospectively analyzed data from 16,243 patients referred for clinical exome sequencing (ES) with a focus on the BAF complex. We applied a genotype-first approach, combining predicted genic constraints to propose candidate
BAFopathy genes.
We identified 127 patients carrying pathogenic variants, likely pathogenic variants, or de novo variants of unknown clinical significance in 11 known
BAFopathy genes. Those include 34 patients molecularly diagnosed using ES reanalysis with new gene-disease evidence (n = 21) or variant reclassifications in known
BAFopathy genes (n = 13). We also identified de novo or predicted loss-of-function variants in 4 candidate
BAFopathy genes, including ACTL6A, BICRA (implicated in Coffin-Siris syndrome during this study), PBRM1, and SMARCC1.
We report the mutational spectrum of BAFopathies in an ES cohort. A genotype-driven and pathway-based reanalysis of ES data identified new evidence for candidate genes involved in BAFopathies. Further mechanistic and phenotypic characterization of additional patients are warranted to confirm their roles in human disease and to delineate their associated phenotypic spectrums.