Abstract：
Coffin-Siris and Nicolaides-Baraitser syndromes are recognizable neurodevelopmental disorders caused by germline variants in BAF complex subunits. The SMARCC2 BAFopathy was recently reported. Herein, we present clinical and molecular data on a large cohort.
Clinical symptoms for 41 novel and 24 previously published affected individuals were analyzed using the Human Phenotype Ontology. For genotype-phenotype correlations, molecular data were standardized and grouped into non-truncating and likely gene-disrupting (LGD) variants. Missense variant protein expression and BAF-subunit interactions were examined using 3D protein modeling, co-immunoprecipitation, and proximity-ligation assays.
Neurodevelopmental delay with intellectual disability, muscular hypotonia, and behavioral disorders were the major manifestations. Clinical hallmarks of BAFopathies were rare. Clinical presentation differed significantly, with LGD variants being predominantly inherited and associated with mildly reduced or normal cognitive development, whereas non-truncating variants were mostly de novo and presented with severe developmental delay. These distinct manifestations and non-truncating variant clustering in functional domains suggest different pathomechanisms. In vitro testing showed decreased protein expression for N-terminal missense variants similar to LGD.
This study improved SMARCC2 variant classification and identified discernible SMARCC2-associated phenotypes for LGD and non-truncating variants, which were distinct from other BAFopathies. The pathomechanism of most non-truncating variants has yet to be investigated.
Clinical symptoms for 41 novel and 24 previously published affected individuals were analyzed using the Human Phenotype Ontology. For genotype-phenotype correlations, molecular data were standardized and grouped into non-truncating and likely gene-disrupting (LGD) variants. Missense variant protein expression and BAF-subunit interactions were examined using 3D protein modeling, co-immunoprecipitation, and proximity-ligation assays.
Neurodevelopmental delay with intellectual disability, muscular hypotonia, and behavioral disorders were the major manifestations. Clinical hallmarks of BAFopathies were rare. Clinical presentation differed significantly, with LGD variants being predominantly inherited and associated with mildly reduced or normal cognitive development, whereas non-truncating variants were mostly de novo and presented with severe developmental delay. These distinct manifestations and non-truncating variant clustering in functional domains suggest different pathomechanisms. In vitro testing showed decreased protein expression for N-terminal missense variants similar to LGD.
This study improved SMARCC2 variant classification and identified discernible SMARCC2-associated phenotypes for LGD and non-truncating variants, which were distinct from other BAFopathies. The pathomechanism of most non-truncating variants has yet to be investigated.
摘要：
目标：Coffin-Siris和Nicolaides-Baraitser综合征，是由BAF复杂亚基中的种系变异引起的可识别的神经发育障碍。最近报道了SMARCC2巴氏病。在这里，我们提供了一个大型队列的临床和分子数据.
方法：使用人类表型本体论分析了41个新的和24个以前发表的受影响个体的临床症状。对于基因型-表型相关性，将分子数据标准化并分组为非截短和可能的基因破坏(LGD)变体.错义变异蛋白表达和BAF亚基相互作用使用3D蛋白建模检查，免疫共沉淀,和邻近连接测定。
结果：智力障碍的神经发育迟缓，肌肉张力减退和行为障碍是主要表现。BAFopathies的临床特征很少见。临床表现有显著差异，LGD变异主要是遗传的，与轻度降低或正常的认知发育有关，而非截短变体大多是从头出现的，并伴有严重的发育迟缓。这些不同的表现和功能域中的非截短变体聚类表明了不同的病理机制。体外测试显示类似于LGD的N末端错义变体的蛋白质表达降低。
结论：这项研究改进了SMARCC2变异分类，并确定了LGD和非截短变异的可识别的SMARCC2相关表型，这与其他的纤维病不同。尚未研究大多数非截短变体的病理机制。
方法：使用人类表型本体论分析了41个新的和24个以前发表的受影响个体的临床症状。对于基因型-表型相关性，将分子数据标准化并分组为非截短和可能的基因破坏(LGD)变体.错义变异蛋白表达和BAF亚基相互作用使用3D蛋白建模检查，免疫共沉淀,和邻近连接测定。
结果：智力障碍的神经发育迟缓，肌肉张力减退和行为障碍是主要表现。BAFopathies的临床特征很少见。临床表现有显著差异，LGD变异主要是遗传的，与轻度降低或正常的认知发育有关，而非截短变体大多是从头出现的，并伴有严重的发育迟缓。这些不同的表现和功能域中的非截短变体聚类表明了不同的病理机制。体外测试显示类似于LGD的N末端错义变体的蛋白质表达降低。
结论：这项研究改进了SMARCC2变异分类，并确定了LGD和非截短变异的可识别的SMARCC2相关表型，这与其他的纤维病不同。尚未研究大多数非截短变体的病理机制。
