MED13L syndrome is a developmental disorder characterized by developmental delay, intellectual disability, and minor differences in facial features. Additionally, some people with this condition have recurrent seizures (epilepsy) or heart abnormalities that are present from birth (congenital heart defects).

Intellectual disability and developmental delay are usually moderate to severe in people with MED13L syndrome. Weak muscle tone (hypotonia) and delayed development of motor skills, such as sitting, standing, and walking, are early symptoms of the condition. After learning to walk, some affected individuals continue to have difficulty with coordination and balance (ataxia). Speech is also delayed, and most people with this condition develop only a few words or never learn to talk. People with MED13L syndrome may exhibit characteristics typical of autism spectrum disorder, including repetitive actions and difficulty with social interactions.

Most people with MED13L syndrome have unusual facial features that consist of a depressed nasal bridge, a bulbous nasal tip, straight eyebrows, outside corners of the eyes that point upward (upslanting palpebral fissures), full cheeks, and an open mouth. Other facial features that sometimes occur are a pronounced double curve of the upper lip (Cupid's bow), and a deep space between the nose and upper lip (philtrum).

Different congenital heart defects can occur in MED13L syndrome. Affected individuals may have transposition of the great arteries, which is abnormal positioning of the large blood vessel that distributes blood from the heart to the rest of the body (aorta) and the artery that carries blood from the heart to the lungs (the pulmonary artery). Other congenital heart defects in MED13L syndrome include a hole between the two lower chambers of the heart (ventricular septal defect), a hole between the two upper chambers of the heart (patent foramen ovale), or a particular combination of heart defects known as tetralogy of Fallot.

As its name suggests, MED13L syndrome is caused by mutations in a gene known as MED13L. This gene provides instructions for making a protein that helps regulate gene activity; it is thought to play an essential role in development both before and after birth. The MED13L gene mutations that cause this condition alter the function of the MED13L protein or reduce the amount of protein present, impairing normal control of gene activity. It is unclear how these changes lead to the particular developmental and physical features of MED13L syndrome.

Normal Function

The MED13L gene provides instructions for making a protein that is one piece (subunit) of a group of proteins known as the mediator complex. This complex regulates the activity (transcription) of genes. Transcription is the first step in the process by which information stored in a gene's DNA is used to build proteins.

The mediator complex physically links the proteins that can turn genes on, called transcription factors, with the enzyme that carries out transcription, called RNA polymerase II. Once transcription factors are attached to RNA polymerase II, transcription begins.

Researchers believe that as part of the mediator complex, the MED13L protein is involved in many aspects of early development, including development of the heart, nerve cells (neurons) in the brain, and structures in the face. The mediator complex plays a role in several chemical signaling pathways within cells. These pathways help direct a broad range of cellular activities, such as cell growth, cell movement (migration), and the process by which cells mature to carry out specific functions (differentiation).

Health Conditions Related to Genetic Changes

MED13L syndrome

More than 50 mutations in the MED13L gene have been found to cause MED13L syndrome. This condition is characterized by moderate to severe developmental delay and intellectual disability and minor differences in facial features. Additionally, some people with MED13L syndrome have recurrent seizures (epilepsy) or heart abnormalities that are present from birth (congenital heart defects).

Some MED13L gene mutations insert or delete regions of DNA within the MED13L gene. These genetic changes lead to a reduction in the total amount of MED13L protein in cells. Other mutations change single protein building blocks (amino acids) in the MED13L protein. It is thought that the altered protein interferes with the function of the normal protein produced from the non-mutated copy of the MED13L gene (such mutations are described as "dominant-negative"). Because dominant negative mutations impair the function of proteins made from both the altered copy of the MED13L gene and the normal copy, individuals with dominant negative mutations tend to have more severe signs than people with mutations that affect protein production from just the altered copy of the gene. While it is likely that mutations in the MED13L gene impair the control of gene activity by the mediator complex, it is unclear how these changes lead to the particular cognitive and physical features of the disorder.

Critical congenital heart disease

MedlinePlus Genetics provides information about Critical congenital heart disease

Other Names for This Gene

• KIAA1025
• MEDIATOR COMPLEX SUBUNIT 13-LIKE
• PROSIT240
• PROTEIN SIMILAR TO TRAP240
• THRAP2
• THYROID HORMONE RECEPTOR-ASSOCIATED PROTEIN 2
• TRAP240-LIKE PROTEIN
• TRAP240L

Genomic Location

MED13L syndrome is inherited in an autosomal dominant pattern, which means one copy of the altered MED13L gene in each cell is sufficient to cause the disorder. Most cases of this condition result from new (de novo) mutations in the gene that occur during the formation of reproductive cells (eggs or sperm) or in early embryonic development. These cases occur in people with no history of the disorder in their family. Very rarely, the condition is inherited from a parent with mosaicism. In these instances, the parent has a MED13L gene mutation in a small number of cells, including reproductive cells (eggs or sperm), and does not show any signs or symptoms of MED13L syndrome.

MED13L syndrome is a rare disorder that occurs in an estimated 1.6 per 100,000 newborns. More than 65 affected individuals have been reported in the scientific literature.