SMARCB1 encodes a subunit of the SWI/SNF complex involved in chromatin remodeling. Pathogenic variants (PV) in this gene can give rise to three conditions. Heterozygous loss-of-function germline PV cause rhabdoid tumor predisposition syndrome and schwannomatosis. Missense PV and small in-frame deletions in exons 8 and 9 result in Coffin-Siris syndrome, which is characterized by intellectual disability (ID), coarse facial features, and fifth digit anomalies.
By a gene matching approach, individuals with a similar SMARCB1 PV were identified. Informed consent was obtained and patient data were collected to further establish genotype-phenotype relationship.
A recurrent de novo missense PV (c.110G>A;p.Arg37His) in exon 2 of SMARCB1, encoding the DNA-binding domain, was identified in four individuals from different genetic centers. They shared a distinct phenotype consisting of profound ID and hydrocephalus due to choroid plexus hyperplasia. Other shared features include severe neonatal feeding difficulties; congenital heart, kidney, and eye anomalies; obstructive sleep apnea; and anemia.
The p.Arg37His PV in the DNA-binding domain of SMARCB1 causes a distinctive syndrome, likely through a gain-of-function or dominant-negative effect, which is characterized by severe ID and hydrocephalus resulting from choroid plexus hyperplasia. This report broadens the phenotypic spectrum associated with PV in SMARCB1 1).
The protein encoded by this gene is part of a complex that relieves repressive chromatin structures, allowing the transcriptional machinery to access its targets more effectively. The encoded nuclear protein may also bind to and enhance the DNA joining activity of HIV-1 integrase. This gene has been found to be a tumor suppressor, and mutations in it have been associated with malignant rhabdoid tumors. Two transcript variants encoding different isoforms have been found for this gene.
Loss of SMARCB1/INI1 expression is considered to be a hallmark for childhood chordomas (CCs). Although mutation/loss of 22q has strongly established the loss of SMARCB1/INI1 in cancers, the cause in CCs remains elusive. Recent studies suggest role of miRNAs in regulation of SMARCB1/INI1 expressions.
Malgulwar et al. examined 5 reported/target predicted miRNAs to SMARCB1/INI1 in SMARCB1/INI1 immunonegative and immunopositive cases, and found upregulation of miR-671-5p and miR-193a-5p in SMARCB1/INI1-immunonegative cases. Notably, these two miRNAs were significantly predicted to target TGF-β signaling, suggestive of dysregulation of developmental and osteoblast regulation pathway in CCs. Overall, we suggest miR-671-5p- and miR-193a-5p-mediated epigenetic mode of SMARCB1/INI1 loss and downregulated TGF-β pathway in CCs 2).