Molecular characteristics

The SMARCB1 gene (MIM #601607) encodes the SMARCB1 protein (a.k.a. SNF5/INI1/BAF47), a core subunit of the BAF swi/snf chromatin remodelling complex.

The condition is autosomal dominant. All reported mutations causing Intellectual Developmental Disorders in SMARCB1 to date have been de novo missense of in frame deletions. The mechanism hypothesised is that of gain of function or dominant-negative effect.

Pathogenic mutations causing Coffin-Siris Syndrome cluster within the SNF5 domain encoded by exons 8 and 9. Recurrent mutations seen in several individuals with CSS include: p.Lys364del, p.Arg366Cys, p.Arg374Gln. Variants of uncertain significance are also reported in exons 5 and 6. Mutations causing loss of protein function do not seem to be associated with Intellectual Developmental Disorder; these are associated with tumour predisposition syndromes.

The intellectual disability with hydrocephalus phenotype is caused by a recurrent missense mutation in exon 2 that affects the DNA-binding domain of SMARCB1 (p.Arg37His).

Diagnostic testing can be performed by Sanger sequencing of SMARCB1 or whole exome/genome sequencing. Variant classification should be according to consensus guidelines (e.g. ACMG guidelines). Mutations are expected to be de novo or inherited from an affected parent. There is a theoretical risk of 50% for the offspring of affected individuals, though given the severity of the neurodevelopmental phenotype no familial cases have been reported to date.