SMC1A

Variants (also called mutations) in the SMC1A gene have been identified in people with Cornelia de Lange syndrome, a developmental disorder that affects many parts of the body. Researchers estimate that variants in this gene account for about 5 percent of all cases of this condition.

Most of the SMC1A gene variants that cause Cornelia de Lange syndrome change single protein building blocks (amino acids) in the SMC1A protein. These variants alter the structure and function of the protein, which likely interferes with the activity of the cohesin complex and impairs its ability to regulate genes that are critical for normal development. Although researchers do not fully understand how these changes cause Cornelia de Lange syndrome, they suspect that altered gene regulation probably underlies many of the developmental problems characteristic of the condition.

Studies suggest that variants in the SMC1A gene tend to cause a form of Cornelia de Lange syndrome with relatively mild features. Compared to variants in the NIPBL gene, which are the most common known cause of the disorder, SMC1A gene variants often cause less significant delays in development and growth and are less likely to cause major birth defects.

Variants in the SMC1A gene have also been identified in infants with a form of X-linked epilepsy. (X-linked refers to the fact that the SMC1A gene is on the X chromosome, one of the two sex chromosomes.) This condition, called developmental and epileptic encephalopathy-85 with or without midline brain defects (or DEE85), appears to affect only females. Affected individuals develop severe, recurrent seizures (epilepsy) by age 2 and have intellectual and developmental impairments. These individuals can also have distinctive facial features.

Most of the SMC1A gene variants that cause DEE85 result in an abnormally short blueprint for making protein. As a result, the blueprint is likely broken down, preventing SMC1A protein production. The gene variants that cause DEE85 severely reduce or eliminate SMC1A protein function in cells. A loss of SMC1A protein function likely interferes with the activity of the cohesin complex and impairs its ability to regulate genes that are critical for normal development. Although researchers do not fully understand how these changes cause DEE85, they suspect that altered gene regulation probably underlies many of the developmental problems characteristic of the condition. It is thought that variants that result in little or no SMC1A protein function cause the more severe signs and symptoms of DEE85, and variants that result in a partially functional version of the protein cause Cornelia de Lange syndrome.