Molecular characteristics

You may find the SMARCB1 gene described using different names – SNF5, INI1 or BAF47. It makes a protein that is part of a large complex that works in cells to open up the genome to allow it to be read.

The condition is autosomal dominant. This means that affected individuals have one normal copy of the SMARCB1 gene, and one copy with a change (mutation). All reported mutations causing learning disability and Coffin-Siris Syndrome have been de novo missense or in frame deletions. Thinking about genes as instructions, these are genetic “spelling” changes, where a single letter is changed (missense), or a single 3 letter word is missing (deletion). With this type of change, the protein made is different. Because SMARCB1 is important for brain and body development, changing the meaning of the genetic instructions causes problems in development.

Several patients have the exact same mutation in the SMARCB1 gene. However, even with the same mutation, they may not share the exact same medical problems. We cannot predict medical problems based on the mutation alone.

To date, all affected individuals result from a de novo SMARCB1 change, i.e. the change happened in the child for the first time and is not present in the father or the mother. Therefore, the chance of that couple having another affected child with the same condition is very low (probably <1%), but greater than that of the general population because of the possibility of germline mosaicism in one of the parents (where some of the maternal egg or paternal sperm cells contain the genetic alteration or chromosome problem).

For a person who has the condition, because they have one normal copy of the gene and one with the mutation, there is a theoretical 50% chance of passing it on should they have children of their own.

Genetic testing for the condition is available in most Genetics centres. This can be performed by a test looking at SMARCB1 alone, though many individuals nowadays are diagnosed using newer technologies (namely exome or genome sequencing) that look at many genes at the same time.

Mutations that cause loss of function (where the protein is not made or doesn’t work at all) do not seem to be associated with learning disability; these cause a distinct condition of familial predisposition to cancer without learning disability.