Institute of Human Genetics, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Berlin Institute of Health at Charitè, Universitätsklinikum Berlin, Centre of Functional Genomics, Berlin, Germany; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
Genet Med. 2023 Nov;25(11):100950. doi: 10.1016/j.gim.2023.100950. Epub 2023 Aug 5.
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.
Coffin-Siris 和 Nicolaides-Baraitser 综合征是由 BAF 复合物亚基种系变异引起的可识别的神经发育障碍。最近报道了 SMARCC2 BAF 病变。在此，我们展示了一个大队列的临床和分子数据。
使用人类表型本体分析了 41 个新的和 24 个先前发表的受影响个体的临床症状。为了进行基因型-表型相关性分析，对分子数据进行了标准化，并分为非截断和可能基因破坏（LGD）变体。使用 3D 蛋白质建模、共免疫沉淀和接近连接测定来检查错义变体蛋白表达和 BAF 亚基相互作用。
神经发育迟缓伴智力残疾、肌肉张力减退和行为障碍是主要表现。BAF 病变的临床特征很少见。临床表现明显不同，LGD 变体主要是遗传性的，与轻度降低或正常认知发育相关，而非截断变体主要是新生的，表现为严重的发育迟缓。这些不同的表现和功能域中非截断变体的聚类表明存在不同的发病机制。体外测试显示，类似于 LGD 的 N 端错义变体的蛋白表达降低。
本研究改进了 SMARCC2 变体分类，并确定了 LGD 和非截断变体的可识别 SMARCC2 相关表型，这些表型与其他 BAF 病变不同。大多数非截断变体的发病机制仍有待研究。
