If a child is diagnosed with Coffin-Siris syndrome due to a SMARCA4 mutation, do they have an increased risk of cancer?

No, individuals diagnosed with Coffin-Siris syndrome linked to SMARCA4 gene variants do not appear to have an increased risk of cancer. The specific types of SMARCA4 mutations associated with Coffin-Siris syndrome are distinct from those linked to cancer predisposition, and the context states that individuals with this condition do not appear to have an increased risk of cancer.

What are the early warning signs of rhabdoid tumors in someone with Rhabdoid Tumor Predisposition Syndrome (RTPS)?

Rhabdoid tumors can develop in various locations, most commonly the brain, spinal cord, or kidneys. Warning signs depend on the

SMARCA4 gene

The SMARCA4 gene provides instructions for making the BRG1 protein, which plays a critical role in chromatin remodeling and acts as a tumor suppressor.

Normal Function

The SMARCA4 gene provides instructions for making a protein called BRG1, which forms one subunit of several SWI/SNF protein complexes. These complexes regulate gene activity through a process known as chromatin remodeling. Chromatin is the network of DNA and protein that packages DNA into chromosomes; by remodeling this structure, the cell can alter how tightly DNA is packaged, thereby regulating gene expression.

The BRG1 protein uses ATP to provide energy for this remodeling. Through their regulation of gene activity, SWI/SNF complexes are involved in essential processes such as repairing damaged DNA, replicating DNA, and controlling the growth, division, and maturation (differentiation) of cells. Consequently, BRG1 and other SWI/SNF subunits are thought to act as tumor suppressors, preventing cells from growing and dividing in an uncontrolled way.

Health Conditions Related to Genetic Changes

Coffin-Siris syndrome

Approximately 40 germline variants in the SMARCA4 gene have been linked to Coffin-Siris syndrome. This condition is characterized by:

Delayed development
Abnormalities of the fifth (pinky) fingers or toes
Characteristic coarse facial features

Researchers suggest these variants result in abnormal chromatin remodeling, which disrupts cellular processes and leads to the diverse symptoms of the syndrome. Individuals with this condition do not appear to have an increased risk of cancer.

Rhabdoid tumor predisposition syndrome

At least six germline variants in the SMARCA4 gene are associated with rhabdoid tumor predisposition syndrome (RTPS). This condition carries a high risk of developing cancerous rhabdoid tumors, typically in the brain, spinal cord, or kidneys. Affected individuals may also develop noncancerous schwannomas, and women are at an increased risk for small cell cancer of the ovary, hypercalcemic type (SCCOHT).

Tumor development in RTPS typically requires a "second hit"—a somatic variant that deletes the remaining normal copy of the SMARCA4 gene in specific cells. This leads to the total absence of the BRG1 protein, impairing its tumor suppressor function.

Other Cancers

Somatic variants in both copies of the SMARCA4 gene can cause noninherited (sporadic) rhabdoid tumors. Additionally, SMARCA4 variants have been identified in:

Lung cancer
SMARCA4-deficiency thoracic sarcomas

It is believed that these variants disrupt SWI/SNF complex function, impairing cell differentiation or gene regulation, which contributes to cancer development.

Other Names for This Gene

ATP-dependent helicase SMARCA4
BAF190
brahma protein-like 1
BRG1
BRG1-associated factor 190A
BRM/SWI2-related gene 1
protein BRG-1
RTPS2
SMCA4_HUMAN
SNF2
SWI2
transcription activator BRG1