SMARCB1

At least 11 variants (also known as mutations) in the SMARCB1 gene have been found to cause Coffin-Siris syndrome. This condition is characterized by delayed development, abnormalities of the fifth (pinky) fingers or toes, and characteristic facial features that are described as coarse. The SMARCB1 gene variants involved in Coffin-Siris syndrome are germline variants, which means that they are present in cells throughout the body. The variants change or remove single protein building blocks (amino acids) in the SMARCB1 protein. Although it is unclear how these changes affect SWI/SNF complexes, researchers suggest that SMARCB1 gene variants result in abnormal chromatin remodeling. Disturbance of this process alters the activity of many genes and disrupts several cell activities, which could explain the diverse signs and symptoms of Coffin-Siris syndrome. People with Coffin-Siris syndrome do not appear to have an increased risk of cancer (see below).

More than 50 germline variants in the SMARCB1 gene have been identified in people with rhabdoid tumor predisposition syndrome (RTPS). RTPS is characterized by a high risk of developing cancerous (malignant) growths called rhabdoid tumors. These tumors most often occur in the brain and spinal cord (central nervous system) or in the kidney, but they can occur in other organs and tissues of the body. Some affected children also develop noncancerous (benign) tumors called schwannomas, which grow on nerves. Women with RTPS are at increased risk of developing a rare type of ovarian cancer called small cell cancer of the ovary, hypercalcemic type (SCCOHT).

In addition to the germline variant affecting one copy of the SMARCB1 gene in each cell, an additional genetic change that deletes the normal copy of the gene is needed for a tumor to develop. This additional change is present only in the cancerous cells. Such changes are known as somatic variants. In combination, the germline and somatic variants lead to the absence or dysfunction of SMARCB1 protein. This deficiency likely impairs the tumor suppressor functions of the proteins, but the specific mechanism that leads to rhabdoid tumors is unknown.

More than two dozen variants in the SMARCB1 gene have been found in people with schwannomatosis, a disorder characterized by multiple noncancerous (benign) tumors called schwannomas that grow on nerves. This type of tumor arises from Schwann cells, which are specialized cells that normally form an insulating layer around the nerve.

SMARCB1 gene variants associated with schwannomatosis lead to production of an altered SMARCB1 protein whose function is reduced but not eliminated. The altered protein is less able to control how cells grow and divide, which can allow tumors to develop. However, it is unknown why these variants are predominantly associated with schwannomas, instead of other tumor types, in people with schwannomatosis.

It appears that germline variants in SMARCB1 alone are not enough to trigger the development of schwannomas. Additional somatic variants that are acquired during a person's lifetime and are present only in certain cells may also be required for schwannomas to form.

Some people who have a variant in the SMARCB1 gene never develop tumors, which is a situation known as reduced penetrance.

Somatic variants in both copies of the SMARCB1 gene, which result in the absence of SMARCB1 protein, cause noninherited (sporadic) rhabdoid tumors in children. As in RTPS (described above), the absence of SMARCB1 protein likely impairs the tumor suppressor functions of the proteins, but the specific mechanism that leads to rhabdoid tumors is unknown.