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 We focus on SMARCB1, including 43 unpublished patients from the EU-RHAB registry and our institution.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

• Authors: Till Holsten, Susanne Bens, Florian Oyen, Karolina Nemes, Martin Hasselblatt, Uwe Kordes, Reiner Siebert, Michael C Frühwald, Reinhard Schneppenheim, Ulrich Schüller
• Journal: European journal of human genetics : EJHG (Eur J Hum Genet) Vol. 26 Issue 8 Pg. 1083-1093 (08 2018) ISSN: 1476-5438 [Electronic] England
• PMID: 29706634 (Publication Type: Journal Article, Meta-Analysis, Research Support, Non-U.S. Gov't, Review)

Chemical References

• SMARCB1 Protein
• SMARCB1 protein, human

Topics

• Abnormalities, Multiple (genetics, pathology)
• Face (abnormalities, pathology)
• Germ-Line Mutation
• Hand Deformities, Congenital (genetics, pathology)
• Humans
• Intellectual Disability (genetics, pathology)
• Meningeal Neoplasms (genetics, pathology)
• Meningioma (genetics, pathology)
• Micrognathism (genetics, pathology)
• Neck (abnormalities, pathology)
• Neurilemmoma (genetics, pathology)
• Phenotype
• Polymorphism, Single Nucleotide
• SMARCB1 Protein (genetics)