EP300-Related Syndrome

EP300-related syndrome happens when there are changes in the EP300 gene. These changes can keep the gene from working as it should.

A related gene called CREBBP has a similar function to the EP300 gene.

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 EP300-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 EP300-related syndrome, the sibling’s risk of having a child who has EP300-related syndrome depends on the sibling’s genes and their parents’ genes.

• If neither parent has the same genetic variant causing EP300-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit EP300-related syndrome.

As of 2024, at least 214 people with EP300-related syndrome have been identified in a medical clinic. Scientists estimate that the condition happens in 1 in 100,000 to 1 in 125,000 live births.

People who have EP300-related syndrome may look different. Appearance can vary and can include some but not all of these features:

• Short height
• A small head, also called microcephaly
• Facial features that are different from those of other family members
• Thick eyebrows
• Wide thumbs that may be positioned differently on the hand
• Big first toes

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:

• Genetics consults
• Development and behavior studies
• Neurological studies
• Orthopedic studies

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 EP300-related syndrome should begin as early as possible, ideally before a child begins school.

People who have EP300-related syndrome may have a higher risk of developing tumors. These may be cancerous or non-cancerous. Your doctor can recommend whether you need additional screening or to consult a specialist.

The information below includes information on Rubinstein-Taybi syndrome (RTS) caused by a variant in EP300. Variants in EP300 that cause Menke-Hennekam syndrome are summarized in the next section below. Variants that cause Menke-Hennekam syndrome are pathogenic missense variants or in-frame deletion variants in exons 30 and 31. Talk to your genetics team to find out what type of variant was identified in your family.

Speech and Learning

Almost all people with RTS EP300-related syndrome had developmental delay or intellectual disability (ID). People had mostly mild ID. People spoke their first words at an average age of 2 years.

• 49 out of 52 people had developmental delay or intellectual disability (94 percent)

Behavior

Some people with RTS EP300-related syndrome had behavioral issues, such as autism, self-injurious behavior, and aggressive behavior. People were often described as motivated to interact with others and ‘overly-friendly’.

• 13 out of 52 people had autism (25 percent)

Brain

Some people with RTS EP300-related syndrome had seizures, and more than one-half of people had non-specific abnormalities on electroencephalogram (EEG). Most had a smaller than average head size, also known as microcephaly. Some people with EP300-related syndrome had brain changes seen on magnetic resonance imaging (MRI).

• 5 out of 52 people had seizures (10 percent)
• 45 out of 52 people had microcephaly (87 percent)

Growth

Some people with RTS EP300-related syndrome were born with heart defects. This includes patent ductus arteriosus, persistent foramen ovale, and atrial and ventricular septal defect.

Often babies had delayed growth after birth, which appeared as a child dropping off the standard growth curve chart. In general, people did not have a growth spurt during puberty. Obesity was a problem for about one in three people.

• 14 out of 52 people had heart defects (27 percent)
• 34 out of 52 people had postnatal growth delay (66 percent)
• 20 out of 52 people had obesity (39 percent)

Gastrointestinal tract and urinary tract issues

It was common for people with RTS EP300-related syndrome to have constipation into adulthood. Some people had urinary tract issues, such as horseshoe kidney, renal duplication, kidney agenesis, kidney dysplasia, hydronephrosis, nephrolithiasis, and vesicoureteral reflux.

• 28 out of 54 people had constipation (52 percent)
• 13 out of 54 people had urinary tract defects (24 percent)

The information below includes information on Menke-Hennekam (MKHK) syndrome caused by a variant in EP300 or CREBBP. Variants in these two genes that cause Menke-Hennekam syndrome are pathogenic missense variants or in-frame deletion variants in exons 30 and 31. Talk to your genetics team to find out what type of variant was identified in your family.

Some researchers organize MKHK into sub-types. The information in this summary does not include sub-types.

Speech and Learning

Almost all people with MKHK syndrome had developmental delay or intellectual disability (ID). People spoke their first words at an average age of 2.6 years.

• 39 out of 40 people had developmental delay or intellectual disability (98 percent)

Behavior

Many people with MKHK syndrome had behavioral issues, such as autism.

• 27 out of 38 people had behavioral issues (71 percent)

Brain

Some people with MKHK syndrome had seizures.

• 7 out of 43 people had seizures (16 percent)

Growth

Some people with MKHK syndrome were born with heart defects. People were often shorter than average, underweight, and had a smaller than average head circumference. Some babies were born premature and were smaller than average at birth.

• 11 out of 42 people had heart defects (26 percent)
• 6 out of 44 babies were born premature (14 percent)

Feeding and digestion

Many people with MKHK syndrome had feeding issues, constipation, and acid reflux.

• 36 out of 43 people had feeding issues (84 percent)
• 20 out of 37 people had constipation (54 percent)
• 16 out of 35 people had acid reflux (46 percent)

Musculoskeletal issues

People with MKHK syndrome had curvature of the spine, both scoliosis and kyphosis. People also had hip dysplasia; higher than average muscle tone and/or lower than average muscle tone; and defects of the extremities, including clubbed feet. Dental defects, including missing teeth, were common.

Vision and hearing issues

Some people with MKHK syndrome had strabismus (crossed eyes), other vision impairments, and hearing impairments.

• 24 out of 40 people had strabismus (60 percent)
• 12 out of 43 people had other vision impairments (28 percent)
• 15 out of 40 people had hearing impairments (38 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 EP300 – www.simonssearchlight.org/research/what-we-study/ep300
• Simons Searchlight EP300 Facebook community – https://www.facebook.com/groups/ep300