PURPOSE: 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.
METHODS: 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.
RESULTS: 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.
CONCLUSION: 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.