By: Sofia Arreguin
MEF2C Genetic Mutation
What is MEF2C?
The Myocyte Enhancer Factor 2C (MEF2C) gene is determined to be a protein-coding gene that manages the order and structure of amino acid chains, which is important for the ability of cells to carry out their functions (National Library of Medicine, 2025). In coding for the MEF2C protein, which is classified as a transcription factor, it serves to activate or deactivate the expression of genes, neuronal growth, and activity at synapses, thereby engaging in maintenance (“What is MEF2C Related Syndrome?,” 2025). This process of encoding the MEF2C protein, or transcription factor, is crucial for the regulation of other genes. Found within the long arm (q) of the 5th chromosome, specifically within the band 14.3, the MEF2C gene is responsible for controlling the expression of other genes throughout the development of the human brain, heart, muscles, and immune system (“MEF2C Haploinsufficiency Syndrome,” n.d.). Essentially, the MEF2C gene carries instructions to build the transcription factor, or the MEF2C protein, which functions to regulate the expression of other genes that are important for the development of our brain and tissues. However, deficiencies or issues with the MEF2C gene can negatively impact the development of the systems, muscles, and organs of the human body.
MEF2C Related to Epilepsy
Recognized by many names, such as 5q14.3 Microdeletion Syndrome, MEF2C-Related Neurodevelopmental Disorder, and MEF2C Haploinsufficiency Syndrome (MCHS), MEF2C deficiency is a rare neurodevelopmental disorder caused by variations or deletions that occur within the 5th chromosome (“MEF2C Deficiency,” 2025). More specifically, variants present in the MEF2C gene or deletions of the amino acid sequences along the 5th chromosome, particularly the 5q14.3 region, and neighboring regulatory regions, such as enhancers, which heighten gene expression, can generate MEF2C Haploinsufficiency (“MEF2C Deficiency,” 2025). From this, genes work less efficiently, resulting in defective or fewer MEF2C proteins and, therefore, reduced activation and activity by other genes, effectively influencing the development of bodily systems. For instance, such enhancer regions are most operative within glial cells. Known for their role in supporting neuronal health, glial cells seem to play an important part in maintaining the nervous system and functionality of the brain; yet disturbances within these cells can result in neurological issues or disorders (“MEF2C Deficiency,” 2025). Likewise, genes that are normally activated, such as MECP2 and CDKL5, by the MEF2C protein no longer perform properly as a result of the protein being dysfunctional or lost. The significance of such genes can be found in the way they both influence gene activity. The MECP2 (Methyl CpG-Binding Protein 2) gene carries instructions to build the MECP2 protein, responsible for maintaining a balance between the excitatory signals elicited by glutamate and inhibitory signals produced by GABA (“MECP2 Gene,” 2017). Similarly, the CDKL5 gene holds instructions for the construction of proteins in cells, and is active in the transmission of signals between neurons, carrying out a similar function as the MECP2 protein (“CDKL5 Gene,” 2020). If these genes are unable to function properly, an imbalance of signals can cause the appearance of seizures, as excitatory signals may not be able to be regulated by the opposing inhibitory signals. This appearance of seizures as co-occurring with MEF2C Haploinsufficiency is quite common and can typically be seen to emerge during the early years of a person’s life. A case revolving around a then 2-year-old male child with a MEF2C variant revealed the onset of atypical febrile seizures at 7 months, targeting one side of the body and consisting of repetitive muscle movements, convulsions as a result of sudden muscle contractions, and brief loss of awareness (Borlot et al., 2019). The child also experienced global developmental delay, which includes the inability to perform certain motor skills, such as sitting, walking, or rolling over, but was able to stand without needing assistance, and verbal skills, such as being able to utter sounds, yet being unable to produce comprehensible words. He also seemed to be overly sensitive to loud sounds, often producing an exaggerated reaction towards them, and was believed to behave and function cognitively at the same degree as a 9-month-old (Borlot et al., 2019).
MEF2C Haploinsufficiency Syndrome
Held within the DNA that forms our genes, cells are known to be necessary for the maintenance of the human body, as the functions they carry out and the roles they play allow the body to work efficiently. All individuals possess multiple genes, inheriting 1 copy from the mother and one copy from the father. These 2 copies of the same gene are known as alleles, and they are usually organized along chromosomes, where they are then enclosed in cells. Oftentimes, a variant or modified allele appears within the offspring, as seen in those with MEF2C Haploinsufficiency syndrome. Its inheritance can be characterized as autosomal dominant, meaning only 1 copy of an altered gene inherited from a parent is sufficient to produce the disorder (“MEF2C Deficiency,” 2025). This is often caused by a heterozygous pathogenic variant, in which the individual inherits 1 ordinary copy of the MEF2C gene from 1 parent, but inherits an altered copy from the other parent (Coleman & Skinner, 2024). However, in most cases, the syndrome develops as a result of a spontaneous change, classifying itself as a de novo variant (“MEF2C Deficiency,” 2025). This signifies that the genetic change is appearing for the first time due to an unplanned mutation occurring within reproductive cells, such as the sperm, egg, or embryo.
Usually appearing during infancy or early childhood, especially during a fever, MEF2C Haploinsufficiency syndrome involves developmental delays, speech disability, hypotonia or low muscle tone, impaired motor skills, gastrointestinal issues, deformed facial features, and seizures (Coleman & Skinner, 2024). Individuals with developmental delay have the ability to speak, but they often produce few words and sentences, and experience a delay in attaining motor skills, such as walking, sitting, or crawling, while gastrointestinal issues often require assistance with eating since many struggle to chew and swallow. Key physical characteristics of MEF2C Haploinsufficiency syndrome include prominent ears, broad foreheads, micrognathia, or a small jaw, and, in some cases, microcephaly or a small head size (Coleman & Skinner, 2024). Other symptoms were also identified to be poor eyesight, including astigmatism, myopia, which only allows individuals to clearly see objects that are close in range, and crossed eyes, skin conditions, such as hemangiomas, which are benign growths of blood vessels that form a red bump within the skin, and respiratory infections (“MEF2C Haploinsufficiency Syndrome,” n.d.). Heart issues have also been reported by medical studies to be characterized as a symptom or consequence of having insufficient MEF2C. Some individuals have been identified to have holes within their heart chambers or between two blood vessels coming from the heart, in a condition known as Patent Ductus Arteriosus (PDA), allowing the blood to flow into the lungs as a result of the unclosed opening (“MEF2C-Related Syndrome,” 2023). Behavioral patterns in individuals with MEF2C Haploinsufficiency syndrome resemble characteristics seen under Autism Spectrum Disorder and consist of stereotypic actions. Such behaviors include repetitive hand movements, such as clapping or flapping, repetitive rocking, head shaking, hyperventilation, an absence of social interaction or eye contact, and hyperkinesis, which involves excessive activity of one’s hands and feet (Coleman & Skinner, 2024). A significant symptom of this syndrome includes epilepsy and seizures, such as absence seizures, involving brief moments of unconsciousness or lack of awareness, focal seizures, affecting certain regions of the brain and body, atonic seizures, consisting of a loss of muscle strength, and infantile spasms. Other seizure types include tonic-clonic seizures, involving shaking limbs and a loss of consciousness, febrile seizures, comprising of convulsions usually triggered by an infection or fever, myoclonic seizures, consisting of sudden and “jerky” movements, and febrile myoclonic seizures, which often occurs during a fever, involving sudden muscle movements and usually ending once the fever reduces the body’s temperature towards its homeostatic state (Coleman & Skinner, 2024).
Diagnosis and Treatment
To help determine the presence of MEF2C deficiencies, genetic testing, Multiplex Ligation-Dependent Probe Amplification (MLPA), Whole Exome Sequencing (WES), or Whole Genome Sequencing (WGS), and electroencephalograms (EEGs) are often employed. For genetic testing, the Chromosomal Microarray (CMA) test is conducted, aiming to identify deletions or variations within the 5th chromosome, specifically in the region that encodes the MEF2C gene (“MEF2C Deficiency,” 2025). However, if the variations are too small and difficult to notice or be detected by the CMA, a more sensitive measure is used: the MLPA. This test can detect small deletions, changes, or duplications of genes that would otherwise be overlooked by other tests (“MEF2C Deficiency,” 2025). The WES testing measure focuses on the protein-coding segments of the gene, looking for any genetic changes, whereas the WGS test analyzes the full genetic code, including both the coding and non-coding protein regions, to uncover any variants or deletions within the gene (“MEF2C Deficiency,” 2025). The EEG test measures and detects abnormal brain activity, which is often associated with the occurrence of seizures.
Although there is no cure for MEF2C deficiency-related disorders, there are treatments and therapies that can help individuals live an improved lifestyle. Visiting an ophthalmologist and audiologist would help manage issues with vision and hearing, respectively, that often arise with the aforementioned disorder (“MEF2C Deficiency,” 2025). Seeing a cardiologist for an electrocardiogram (EKG), which measures the heart’s rhythm, or an echocardiogram (ECHO), which focuses on the heart’s structure, could be beneficial for maintaining heart health, such as heart rate and blood pressure. Receiving EEG testing could help individuals manage their epilepsy, allowing doctors to determine the type of seizures they experience and which medications could be of most benefit. For better management of behavioral issues or patterns, visiting a psychiatrist is advised, and visiting speech and physical therapy sessions is recommended to treat verbal and motor delays. If recurring, individuals could visit an immunologist to treat the infections, and, if relevant, visit a dermatologist to treat their hemangiomas (“MEF2C Deficiency,” 2025).
While considered to be a rare genetic condition, there is still ongoing research to bring in more knowledge and, therefore, more treatments that can benefit affected individuals. Although there is no definitive treatment created solely for this condition, it is important to note that there are therapies available to help those with MEF2C-related epilepsy, or MEF2C Haploinsufficiency syndrome, live a more enhanced lifestyle.
References
Borlot, F., Whitney, R., Cohn, R. D., & Weiss, S. K. (2019). MEF2C-related epilepsy: Delineating the phenotypic spectrum from a novel mutation and literature review. Seizure, 67, 86–90. https://doi.org/10.1016/j.seizure.2019.03.015
Coleman, J. C., & Skinner, S. A. (2024, December 12). MEF2C-Related Disorder. In GeneReviews [Internet]. https://www.ncbi.nlm.nih.gov/books/NBK610216/
MEF2C Deficiency (2025). NORD (National Organization for Rare Disorders). https://rarediseases.org/rare-diseases/mef2c-deficiency/
MEF2C Haploinsufficiency Syndrome. (n.d.) Unique | Understanding Chromosome & Gene Disorders. https://www.rarechromo.org/media/information/Chromosome%20%205/MEF2C%20haploinsufficiency%20syndrome%20QFN.pdf
National Library of Medicine, National Center for Biotechnology Information. (2025, November 25). Gene (Gene ID: 4208) [Data File]. Retrieved from https://www.ncbi.nlm.nih.gov/gene/4208
Simons Searchlight | MEF2C-Related Syndrome. (2023, November 30). Simons Searchlight. https://www.simonssearchlight.org/gene-guide/mef2c/
U.S. National Library of Medicine. (2020). CDKL5 gene: MedlinePlus Genetics. MedlinePlus. https://medlineplus.gov/genetics/gene/cdkl5/#conditions
U.S. National Library of Medicine. (2017). MECP2 gene: MedlinePlus Genetics. MedlinePlus. https://medlineplus.gov/genetics/gene/mecp2/#conditions
What is MEF2C Related Syndrome?. (2025). US MEF2C Foundation. https://www.usmef2cfoundation.org/mef2crelatedsyndrome
