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 We focus on SMARCB1, including 43 unpublished patients from the EU-RHAB registry and our institution.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.

Fig. 1

Distribution and type of germline variants occuring along the SMARCB1 gene. On the left side, variants causing benign entities are indicated in violet (schwannoma), yellow (meningioma), and green (Coffin–Siris syndrome), while the right side shows malignancies in red (rhabdoid tumor) and light blue (CRINET). Red bars show extent of deletions and duplications. Note that variants in benign disorders are mainly present in 1, 2, 8, and 9, while malignant tumors are frequently caused by variants within exons 2–7. Light blue bars indicate for known domains