Heterozygous variants in BICRA and BICRAL, sub-units of ncBAF complex, cause neurodevelopmental disorders in human.

Abstract

Background/Objectives: SWI/SNF-related intellectual disability disorders (SSRIDDs) are rare neurodevelopmental disorders caused by variants in several members of SWI/SNF chromatin-remodeling complexes. A new ncBAF complex with unique core subunits BICRA (a.k.a. GLTSCR1) and its homolog BICRAL (a.k.a. GLTSCR1L) were recently discovered. Interestingly we previously showed that variants in BICRA cause a unique SSRIDD in human. Method(s): Through international collaborations, we collected clinical data of 33 additional individuals carrying variants in BICRA and 5 individuals with variants in BICRAL. Blood-derived DNA was used to generate an episignature. Human embryonic stem cells based disease models were generated and differentiated towards neural stem cells and excitatory neurons, followed by RNA-sequencing and morphology analysis. Result(s): Individuals carrying rare variants in BICRA present with neurodevelopmental phenotypes, including intellectual disability, developmental delay, autism spectrum disorders and behavioral abnormalities as well as dysmorphic features. Similarly, individuals with variants BICRAL, showed overlapping clinical phenotypes. A predominantly hypomethylated DNA methylation profile was identified in patients with pathogenic BICRA variants. The RNA-sequencing analysis revealed that either reduced BICRAL or complete absence of BICRA leads to transcriptome change in neural stem cells, altering pathways related to axon guidance. Both BICRA and BICRAL haploinsufficiency result in morphologically increased branching and decreased neurites' length in excitatory neurons. Conclusion(s): Our findings showed that haploinsufficiency of both BICRA and BICRAL are causes of NDDs, that are related to a specific episignature. Furthermore, our functional studies provide insights in the pathomechanisms of these novel NDDs.