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.

Choroid plexus hyperplasia, Hydrocephalus, Intellectual disability, Recurrent pathogenic variant, SMARCB1
dx.doi.org/10.1038/s41436-018-0079-4, hdl.handle.net/1765/108877
Genetics in Medicine
Erasmus MC: University Medical Center Rotterdam

Diets, I.J. (Illja J.), Prescott, T, Champaigne, N.L. (Neena L.), Mancini, G.M.S, Krossnes, B. (Bård), Frič, R. (Radek), … Kleefstra, T. (2018). A recurrent de novo missense pathogenic variant in SMARCB1 causes severe intellectual disability and choroid plexus hyperplasia with resultant hydrocephalus. Genetics in Medicine, (21), 572–579. doi:10.1038/s41436-018-0079-4