EBF3-Related Syndrome

This guide is not meant to take the place of medical advice. Please consult with your doctor about your genetic results and health care choices. This Gene Guide was last updated on 2024. As new information comes to light with new research we will update this page. You may find it helpful to share this guide with friends and family members or doctors and teachers of the person who has EBF3-Related Syndrome.
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EBF3-related syndrome is also called EBF3 neurodevelopmental disorder or Hypotonia, Ataxia, and Delayed Development Syndrome (HADDS). For this webpage, we will be using the name EBF3-related syndrome to encompass the wide range of variants observed in the people identified.

EBF3-related syndrome happens when there are changes to the EBF3 gene. These changes can keep the gene from working as it should.

Key Role

The EBF3 gene plays a key role in the growth of brain cells.


Because the EBF3 gene is important in the development and function of brain cells, many people who have EBF3-related syndrome have:

  • Developmental delay
  • Intellectual disability
  • Low muscle tone
  • Autism, or attention deficit hyperactivity disorder, also called ADHD, or both
  • Genitourinary defects
  • Gastrointestinal issues
  • Musculoskeletal issues

Our genes contain the instructions, or code, that tell our cells how to grow, develop, and work. Every child gets two copies of the EBF3 gene: one copy from their mother, from the egg, and one copy from their father, from the sperm. In most cases, parents pass on exact copies of the gene to their child. But the process of copying genes is not perfect. A change in the genetic code can lead to physical issues, developmental issues, or both.

Sometimes a random change happens in the sperm or egg. This change to the genetic code is called a ‘de novo’, or new, change. The child can be the first in the family to have the gene change.

De novo changes can take place in any gene. We all have some de novo changes, most of which don’t affect our health. But because EBF3 plays a key role in development, de novo changes in this gene can have a meaningful effect.

Research shows that EBF3-related syndrome is often the result of a de novo change in EBF3. Many parents who have had their genes tested do not have the EBF3 gene change found in their child who has the syndrome. In some cases, EBF3-related syndrome happens because the gene change was passed down from a parent. This is called dominant inheritance.

Dominant Inheritance

Children have a 50% chance of inheriting the genetic change

Autosomal Dominant Genetic Syndrome

GENE / gene
GENE / gene
Genetic variant that happens in sperm or egg, or after fertilization
GENE / gene
Child with de novo genetic variant
gene / gene
Non-carrier child
gene / gene
Non-carrier child

Why does my child have a change in the EBF3 gene?

No parent causes their child’s EBF3-related syndrome. We know this because no parent has any control over the gene changes that they do or do not pass on to their children. Please keep in mind that nothing a parent does before or during the pregnancy causes this to happen. The gene change takes place on its own and cannot be predicted or stopped.

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 EBF3-related syndrome depends on the genes of both birth parents.

  • If neither birth parent has the same gene change 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 change in the gene.
  • If one birth parent has the same gene change found in their child, the chance of having another child who has the syndrome is 50 percent.

For a symptom-free sibling, a brother or sister, of someone who has EBF3-related syndrome, the risk of having a child who has the syndrome depends on the symptom-free sibling’s genes and their parents’ genes.

  • If neither parent has the same gene change found in their child who has the syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who has EBF3-related syndrome.
  • If one birth parent has the same gene change found in their child who has the syndrome, the symptom-free sibling has a small chance of also having the same gene change. If the symptom-free sibling has the same gene change as their sibling who has the syndrome, the symptom-free sibling’s chance of having a child who has EBF3-related syndrome is 50 percent.

For a person who has EBF3-related syndrome, the risk of having a child who has the syndrome is about 50 percent.

As of 2024, at least 99 people with EBF3-related syndrome have been identified in a medical clinic, and about 50 have been described in medical research. The first case of EBF3-related syndrome was described in 2017.

People who have EBF3-related syndrome may look different. Appearance can vary and can include some but not all of these features:

  • Certain facial features, including a triangular face
  • Shorter than average height
  • Single connected eyebrow, also called synophrys
  • Small ears
  • Roof of the mouth that is highly arched
  • Crowded teeth
  • Single crease on the palms of hands

Scientists and doctors have only just begun to study EBF3-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 EBF3-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:

This section includes a summary of information from major published articles. It highlights how many people have different symptoms. To learn more about the articles, see the Sources and references section of this guide.

The section includes medical information on about 66 people with EBF3-related syndrome described in research publications.

Speech and Learning

All people with EBF3-related syndrome had intellectual disability or developmental delay. Most people had speech delays.

  • 66 out of 66 people had intellectual disability or developmental delay (100 percent)
  • 18 out of 21 people had speech delay (86 percent)


Some people had autism, features of autism, or attention deficit hyperactivity disorder (ADHD). Other behavioral changes, like self-harming behavior, were also reported. Some people had decreased pain sensitivity.

  • 6 out of 51 people had autism (12 percent)
  • 13 out of 51 people had ADHD (26 percent)
  • 7 out of 51 people had decreased pain sensitivity (14 percent)
6 out of 51 people had autism.
13 out of 51 people had ADHD.
7 out of 51 people had decreased pain sensitivity.


Some people had brain changes seen on magnetic resonance imaging (MRI).

  • 19 out of 66 people had abnormal findings on MRI (29 percent)

Sitting, walking, muscle tone, and motor concerns

Low muscle tone and ataxia were very common. Almost all did not meet developmental milestones.


About one-quarter of people had growth issues, like shorter than average height and head size.

  • 14 out of 56 people had short height and smaller than average head size (25 percent)

Other body systems

Some people had gastrointestinal issues, like constipation, difficulty swallowing, gastroesophageal reflux, and frequent vomiting. Musculoskeletal issues included: concave chest; sideways curve of the spine, also called scoliosis; webbing of the second and third toes; and bilateral club foot.

Several people had urogenital issues, including renal dysplasia, undescended testes, bicornuate uterus, lack of bladder control, and vesicoureteral reflux.

Eye issues were common and included nearsightedness or crossed eyes, also called strabismus.

  • 13 out of 51 people had gastrointestinal issues (26 percent)
  • 14 out of 51 people had musculoskeletal issues (28 percent)
  • 19 out of 59 people had urogenital issues (32 percent)
  • 12 out of 14 people had strabismus (86 percent)
13 out of 51 people had gastrointestinal issues.
14 out of 51 people had musculoskeletal issues.
19 out of 59 people had urogenital issues.
12 out of 14 people had strabismus.

Where can I find support and resources?

EBF3-HADDS Foundation

The EBF3-HADDS Foundation was created to enhance the lives of people with HADDS through research, education, support, and advocacy.

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 and click “Join Us.”

Sources and References

The content in this guide comes from published studies about EBF3-related syndrome. Below you can find details about each study, as well as links to summaries or, in some cases, the full article.

  • Harms FL. et al. American Journal of Human Genetics, 100, 117-127, (2017). Mutations in EBF3 disturb transcriptional profiles and cause intellectual disability, ataxia, and facial dysmorphism
  • Tanaka AJ. et al. Cold Spring Harbor Molecular Case Studies, a002097, 3, (2017). De novo variants in EBF3 are associated with hypotonia, developmental delay, intellectual disability, and autism
  • Zhu, J., Li, W., Yu, S., Lu, W., Xu, Q., Wang, S., Qian, Y., Guo, Q., Xu, S., Wang, Y., Zhang, P., Zhao, X., Ni, Q., Liu, R., Li, X., Wu, B., Zhou, S., & Wang, H. (2023). Further delineation of EBF3-related syndromic neurodevelopmental disorder in twelve Chinese patients. Frontiers in Pediatrics, 11, 1091532.
  • Narayanan D. L., Kutsche K., & Girisha K. M. EBF3 Neurodevelopmental Disorder. 2021 May 6. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from:
  • Ciaccio, C., Pantaleoni, C., Moscatelli, M., Chiapparini, L., Nigro, V., Valente, E. M., Sciacca, F., Canafoglia, L., Bulgheroni, S., & D’Arrigo, S. (2023). Neurologic, neuropsychologic, and neuroradiologic features of EBF3-related syndrome. Neurology Genetics, 9(2), e200049.
  • Nishi, E., Uehara, T., Yanagi, K., Hasegawa, Y., Ueda, K., Kaname, T., Yamamoto, T., Kosaki, K., & Okamoto, N. (2021). Clinical spectrum of individuals with de novo EBF3 variants or deletions. American Journal of Medical Genetics Part A, 185(10), 2913-2921.

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