Germline variants in SMARCB1 and other members of the BAF chromatin-remodeling complex across human disease entities: a meta-analysis

Abstract

Germline variants that affect function are found in seven genes of the BAF chromatin-remodeling complex. They are linked to a broad range of diseases that, according to the gene affected, range from non-syndromic or syndromic neurodevelopmental disorders to low-grade tumors and malignancies. In the current meta-analysis, we evaluate genetic and clinical data from more than 400 families and 577 patients affected by BAF germline alterations. We focus on SMARCB1, including 43 unpublished patients from the EU-RHAB registry and our institution. For this gene, we further demonstrate whole gene as well as exon deletions and truncating variants to be associated with malignancy and early-onset disease. In contrast, non-truncating variants are associated with non-malignant disorders, such as Coffin-Siris syndrome or late-onset tumors like schwannoma or meningioma (p < 0.0001). SMARCB1 germline variants are distributed across the gene with variants in exons 1, 2, 8, and 9 being associated with low-grade entities, and single-nucleotide variants or indels outside of exon 9 that appear in patients with malignancies (p < 0.001). We attribute variants in specific BAF genes to certain disease entities. Finally, single-nucleotide variants and indels are sometimes detected in the healthy relatives of tumor patients, while Coffin-Siris syndrome and Nicolaides-Baraitser syndrome generally seem to appear de novo. Our findings add further information on the genotype-phenotype association of germline variants detected in genes of the BAF complex. Functional studies are urgently needed for a deeper understanding of BAF-related disorders and may take advantage from the comprehensive information gathered in this article.

Atypical teratoid/rhabdoid tumors (ATRTs) with SMARCA4 mutation are molecularly distinct from SMARCB1-deficient cases

“…About one-third of patients with SMARCB1-deficient MRTs carry germline mutations within the SMARCB1 gene [3,7,20]. Although based on very small numbers, it appears as if patients with an ATRT-SMARCA4 are even more often carriers of germline mutations.…”

Study of chromatin remodeling genes implicates SMARCA4 as a putative player in oncogenesis in neuroblastoma

“…Recent reports have highlighted chromatin remodeling as an important player in oncogenesis, with the main mechanisms of action consisting in tumor suppression, but variations in CRG/EMGs might also play a role in oncogenesis via gain of function . CRG alterations have previously been identified in NB patients, targeting ARIDs , ATRX , DAXX or SMARCA4 …”

“…SMARCA4 has been shown to play a role in the oncogenesis of different tumors and thus are not specific to NB. Indeed, germline alterations in SMARCA4 conferring predisposition to SCCOHT and RT . At a somatic level, missense point mutations in SMARCA4 mapping to the ATPase domain might cause loss of direct binding between BAF and PRC1 which could contribute to oncogenesis or epigenetic plasticity during tumor development .…”

“…Indeed, germline alterations in SMARCA4 conferring predisposition to SCCOHT and RT. 39,44,45 At a somatic level, missense point mutations in SMARCA4 mapping to the ATPase domain might cause loss of direct binding between BAF and PRC1 which could contribute to oncogenesis or epigenetic plasticity during tumor development. 46 Such SMARCA4 missense point mutations have been described in medulloblastoma.…”

Beyond the Exome: The Non-coding Genome and Enhancers in Neurodevelopmental Disorders and Malformations of Cortical Development

“…Aberrations in many of the steps described above can result in genetic disorders. For example, in recent years a large number of disorders have been described that are caused by mutations in chromatin modifying enzymes or proteins involved in 3D chromatin regulation (Gregor et al, 2013; Ball et al, 2014; Mirabella et al, 2016; Holsten et al, 2018). Given the complexity of gene regulation and the many contributing factors acting at different stages of this process, it seems likely that many more will be discovered in the near future.…”