ARID1A

More than 30 variants (also known as mutations) in the ARID1A 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 ARID1A gene variants involved in Coffin-Siris syndrome lead to an abnormally short, nonfunctional protein. As a result, affected individuals have half the normal amount of functioning ARID1A protein. Although it is unclear how these changes affect SWI/SNF complexes, researchers suggest that ARID1A gene variants 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).

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Variants in the ARID1A gene have been found in many types of cancer, including cancers of the ovaries and lining of the uterus (endometrium) in women and cancers of the kidney, stomach, bladder, lung, breast, and brain. These variants are somatic, which means they are acquired during a person's lifetime and are present only in tumor cells. The mechanism by which variants in the ARID1A gene contribute to cancer 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 ARID1A gene variants are necessary for cancer development.