KMT2E-Related Syndrome

KMT2E-related syndrome happens when there are changes in the KMT2E gene. These changes can keep the gene from working as it should.

Each family is different. A geneticist or genetic counselor can give you advice on the chance that this will happen again in your family.

The risk of having another child who has KMT2E-related syndrome depends on the genes of both biological parents. 

• If neither biological parent has the same genetic variant found in their child, the chance of having another child who has the syndrome is on average 1 percent. This 1 percent chance is higher than the chance of the general population. The increase in risk is due to the very unlikely chance that more of the mother’s egg cells or the father’s sperm cells carry the same genetic variant. 
• If one biological parent has the same genetic variant found in their child, the chance of having another child who has the syndrome is 50 percent. 

For a symptom-free brother or sister of someone who has KMT2E-related syndrome, the sibling’s risk of having a child who has KMT2E-related syndrome depends on the sibling’s genes and their parents’ genes. 

• If neither parent has the same genetic variant causing KMT2E-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit KMT2E-related syndrome. 

As of 2025, more than 120 people with KMT2E-related syndrome have been identified in medical research.

People who have KMT2E-related syndrome may look different. Features are usually subtle and nonspecific and no recognizable pattern has been found. Facial features can include some or all of the following:

• Elongated head shape, also called dolichocephaly
• Long forehead
• Deep-set eyes
• Swelling in the tissue surrounding the eyes, also called periorbital fullness
• Noticeable cheekbones, also called malar prominence
• Noticeable folds from the nose to the mouth, also called prominent nasolabial folds

Scientists and doctors have only just begun to study KMT2E-related syndrome. At this point, there are no medicines designed to treat the syndrome. A genetic diagnosis can help people decide on the best way to track the condition and manage therapies. Doctors can refer people to specialists for:

• Physical exams and brain studies
• Genetics consults
• Development and behavior studies
• Other issues, as needed

A developmental pediatrician, neurologist, or psychologist can follow progress over time and can help:

• Suggest the right therapies. This can include physical, occupational, speech, or behavioral therapy.
• Guide individualized education plans (IEPs).

Specialists advise that therapies for KMT2E-related syndrome should begin as early as possible, ideally before a child begins school.

If seizures happen, consult a neurologist. There are many types of seizures, and not all types are easy to spot. To learn more, you can refer to resources such as the Epilepsy Foundation’s website: www.epilepsy.com/learn/types-seizures.

Researchers have found different pathogenic variants in the KMT2E gene. Most were protein-truncating variants (where the protein is shorter in length than normal, which prevents it from working properly).

A smaller group of about five people had missense variants (where one building block of the protein is swapped for another). These people had more severe symptoms.

Learning

Most people with KMT2E-related syndrome had global developmental delay and/or mild to moderate intellectual disabilities.

• 56 out of 58 people had global developmental delay (97 percent)
• 31 out of 37 people had intellectual disability (84 percent)

Behavior

People with KMT2E-related syndrome had behavioral issues, such as autism spectrum disorder, and sleep issues like frequent waking and/or difficulty falling asleep. Some people had skin-picking behavior, anxiety, aggression, self-injury behavior, and sensory issues.

• 18 out of 47 people had autism spectrum disorder (38 percent)
• 8 out of 17 people had sleep issues (47 percent)

Brain

People with KMT2E-related syndrome had low muscle tone (hypotonia), brain changes seen on magnetic resonance imaging (MRI), seizures, and a larger then average head size (macrocephaly). People with pathogenic missense variants had a smaller than average head size (microcephaly) and more severe seizures than those with pathogenic protein-truncating variants. See points and graph below.

• 23 out of 50 people had hypotonia (46 percent)
• 27 out of 43 people had brain changes seen on MRI (63 percent)
• 16 out of 56 people had seizures (29 percent)
• 29 out of 52 people had macrocephaly (56 percent)
• 3 out of 5 people had microcephaly in people with pathogenic missense variants (60 percent)

Gastrointestinal

Almost one-half of people with KMT2E-related syndrome had gastrointestinal issues like constipation, reflux, vomiting and/or reduced bowel motility.

• 20 out of 45 people had gastrointestinal issues (44 percent)

Simons Searchlight

Simons Searchlight is an online international research program, building an ever growing natural history database, biorepository, and resource network of over 175 rare genetic neurodevelopmental disorders. By joining their community and sharing your experiences, you contribute to a growing database used by scientists worldwide to advance the understanding of your genetic condition. Through online surveys and optional blood sample collection, they gather valuable information to improve lives and drive scientific progress. Families like yours are the key to making meaningful progress. To register for Simons Searchlight, go to the Simons Searchlight website at www.simonssearchlight.org and click “Join Us.”

• Learn more about Simons Searchlight: www.simonssearchlight.org/frequently-asked-questions

• Simons Searchlight webpage with more information on KMT2E: www.simonssearchlight.org/research/what-we-study/KMT2E

• Simons Searchlight KMT2E Facebook community: https://www.facebook.com/groups/kmt2e