2.1. Coffin-Siris syndrome

At least 16 mutations in the SMARCA4 gene can 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 SMARCA4 gene mutations involved in Coffin-Siris syndrome are germline mutations, which means that they are present in cells throughout the body. The mutations change single protein building blocks (amino acids) in or remove an amino acid from the BRG1 protein. Although it is unclear how these changes affect SWI/SNF complexes, researchers suggest that SMARCA4 gene mutations result in abnormal chromatin remodeling. Disturbance of this process alters the activity of many genes and disrupts several cellular processes, 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).

2.2. habdoid tumor predisposition syndrome

At least six germline mutations in the SMARCA4 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 mutation affecting one copy of the SMARCA4 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 mutations. In combination, the germline and somatic mutations lead to the absence of BRG1 protein. This absence likely impairs the tumor suppressor functions of the protein, but the specific mechanism that leads to rhabdoid tumors is unknown.

2.3. Other cancers

Somatic mutations in both copies of the SMARCA4 gene, which result in the absence of SMARCA4 protein, cause noninherited (sporadic) rhabdoid tumors in children. Somatic mutations in the SMARCA4 gene have also been found in certain other types of cancer, particularly lung cancer and other cancers in the chest called SMARCA4-deficiency thoracic sarcomas. The mechanism by which mutations in the SMARCA4 gene contribute to these tumors is unknown, although it is thought that changes in SWI/SNF complexes are involved. These changes may impair normal cell differentiation, which leads to the overgrowth of certain cell types, causing cancer. Alternatively, abnormal SWI/SNF complexes may disrupt the regulation of genes that help control the growth and division of cells, which leads to cancer. It is likely that other genetic changes in addition to SMARCA4 gene mutations are necessary for cancer development.