SWI/SNF-related intellectual disability disorders (SSRIDDs) are rare neurodevelopmental disorders characterized by developmental disability, coarse facial features, and fifth digit/nail hypoplasia that are caused by pathogenic variants in genes that encode for members of the SWI/SNF (or BAF) family of chromatin remodeling complexes. We have identified 12 individuals with rare variants (10 loss-of-function, 2 missense) in the BICRA (BRD4 interacting chromatin remodeling complex-associated protein) gene, also known as GLTSCR1, which encodes a subunit of the non-canonical BAF (ncBAF) complex. These individuals exhibited neurodevelopmental phenotypes that include developmental delay, intellectual disability, autism spectrum disorder, and behavioral abnormalities as well as dysmorphic features. Notably, the majority of individuals lack the fifth digit/nail hypoplasia phenotype, a hallmark of most SSRIDDs. To confirm the role of BICRA in the development of these phenotypes, we performed functional characterization of the zebrafish and Drosophila orthologs of BICRA. In zebrafish, a mutation of bicra that mimics one of the loss-of-function variants leads to craniofacial defects possibly akin to the dysmorphic facial features seen in individuals harboring putatively pathogenic BICRA variants. We further show that Bicra physically binds to other non-canonical ncBAF complex members, including the BRD9/7 ortholog, CG7154, and is the defining member of the ncBAF complex in flies. Like other SWI/SNF complex members, loss of Bicra function in flies acts as a dominant enhancer of position effect variegation but in a more context-specific manner. We conclude that haploinsufficiency of BICRA leads to a unique SSRIDD in humans whose phenotypes overlap with those previously reported.

SWI/SNF 相关智力障碍 (SSRIDD) 是一种罕见的神经发育障碍，其特征是发育障碍、面部特征粗糙和第五指/指甲发育不全，由编码 SWI/SNF（或 BAF）成员的基因的致病性变异引起) 染色质重塑复合物家族。我们已经鉴定出 12 个人的BICRA （ BRD4 相互作用染色质重塑复合体相关蛋白）基因（也称为GLTSCR1 ）具有罕见变异（10 个功能丧失，2 个错义），该基因编码非典型 BAF 的一个亚基（ ncBAF）复合物。这些人表现出神经发育表型，包括发育迟缓、智力障碍、自闭症谱系障碍、行为异常以及畸形特征。值得注意的是，大多数人缺乏第五指/指甲发育不全表型，这是大多数 SSRIDD 的标志。为了证实 BICRA 在这些表型发展中的作用，我们对 BICRA 的斑马鱼和果蝇直系同源物进行了功能表征。在斑马鱼中，模仿其中一种功能丧失变异的Bicra突变会导致颅面缺陷，可能类似于在携带假定致病性BICRA变异的个体中看到的畸形面部特征。我们进一步表明 Bicra 与其他非经典 ncBAF 复合体成员物理结合，包括 BRD9/7 直系同源物 CG7154，并且是果蝇中 ncBAF 复合体的定义成员。与其他 SWI/SNF 复合体成员一样，果蝇中Bicra功能的丧失是位置效应杂色的主要增强剂，但以更具体的方式进行。 我们得出的结论是， BICRA的单倍体不足导致人类出现独特的 SSRIDD，其表型与之前报道的表型重叠。