GENE GUIDE

RFX3-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 in 2025. 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 RFX3-Related Syndrome.
a doctor sees a patient

RFX3-related syndrome happens when there are changes in the RFX3 gene. These changes can keep the gene from working as it should.

Key Role

The RFX3 gene plays a role in human development.

Symptoms

Because the RFX3 gene is important for brain activity, many people who have RFX3-related syndrome have:

  • Intellectual disability
  • Seizures
  • Autism
  • Attention-deficit/hyperactivity disorder (ADHD)
  • Larger than average head size, also called macrocephaly
  • Smaller than average head size, also called microcephaly

RFX3-related syndrome is a genetic condition, which means that it is caused by variants in genes. Our genes contain the instructions, or code, that tell our cells how to grow, develop, and work. Every child gets two copies of the RFX3 gene: one copy from their mother’s egg, and one copy from their father’s sperm. In most cases, parents pass on exact copies of the gene to their child. But the process of creating the egg or sperm is not perfect. A change in the genetic code can lead to physical issues, developmental issues, or both. 

Sometimes a spontaneous variant happens in the sperm, egg or after fertilization. When a brand new genetic variant happens in the genetic code is called a ‘de novo’ genetic variant. The child is usually the first in the family to have the genetic variant.

De novo variants can take place in any gene. We all have some de novo variants, most of which don’t affect our health. But because RFX3 plays a key role in development, de novo variants in this gene can have a meaningful effect. 

Research shows that RFX3-related syndrome is often the result of a de novo variant in RFX3. Many parents who have had their genes tested do not have the RFX3 genetic variant found in their child who has the syndrome. In some cases, RFX3-related syndrome happens because the genetic variant was passed down from a parent.

Autosomal dominant conditions

RFX3-related syndrome is an autosomal dominant genetic condition. This means that when a person has the one damaging variant in RFX3 they will likely have symptoms of RFX3-related syndrome. For someone with an autosomal dominant genetic syndrome, every time they have a child there is a 50 percent chance they pass on the same genetic variant and a 50 percent chance they do not pass on the same genetic variant.

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

No parent causes their child’s RFX3-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 foreseen 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 RFX3-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 RFX3-related syndrome, the sibling’s risk of having a child who has RFX3-related syndrome depends on the sibling’s genes and their parents’ genes. 

  • If neither parent has the same genetic variant causing RFX3-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit RFX3-related syndrome. 
  • If one biological parent has the same genetic variant causing RFX3-related syndrome, the symptom-free sibling has a 50 percent chance of also having the same genetic variant. If the symptom-free sibling has the same genetic variant, their chance of having a child who has the genetic variant is 50 percent. 

For a person who has RFX3-related syndrome, the risk of having a child who has the syndrome is about 50 percent.

As of 2024, at least 19 people with RFX3-related syndrome have been described in medical research.

People who have RFX3-related syndrome may look different. Appearance can vary and can include some but not all of these features:

  • Wide nasal bridge
  • Roof of mouth with a high arch
  • Hand and foot defects, such as polydactyly in which there are one or more extra fingers

Scientists and doctors have only just begun to study RFX3-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 RFX3-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: epilepsy.com/learn/types-seizures.

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.

Speech and learning

People with RFX3-related syndrome had developmental delay or intellectual disability, and some had speech delay.

  • 17 out of 19 people had developmental delay or intellectual disability (90 percent)
  • 12 out of 16 people had speech delay (75 percent)

Behavior

People with RFX3-related syndrome had behavioral issues, including autism, attention-deficit/hyperactivity disorder (ADHD), mood swings, anxiety, aggression, sensory hypersensitivity, self-injury, or oppositional behavior.

  • 11 out of 13 people had behavioral issues (85 percent)
  • 14 out of 16 people had autism (88 percent)
  • 10 out of 13 people had ADHD (77 percent)
85%
11 out of 13 people had behavioral issues.
88%
14 out of 16 people had autism.
77%
10 out of 13 people had ADHD.

Brain

Some people with RFX3-related syndrome had seizures, brain changes observed on magnetic resonance imaging (MRI), and a larger than average head size, also called macrocephaly. Two people had a smaller than average head size, also called microcephaly. Some people over the age of 15 had cognitive or behavioral decline, and two people had hallucinations in adulthood.

  • 4 out of 15 people had seizures (27 percent)
  • 4 out of 8 people had brain changes observed on MRI (50 percent)
  • 6 out of 12 people had macrocephaly (50 percent)
Human head showing brain outline
27%
4 out of 15 people had seizures.
50%
4 out of 8 people had brain changes observed on MRI.
50%
6 out of 12 people had macrocephaly.

Vision

Some people with RFX3-related syndrome had vision problems, including crossed eyes (strabismus) or nearsightedness (myopia).

Sleep

Sleep difficulties included limited total duration of sleep, frequent awakenings, or early morning awakenings.

  • 8 out of 10 people had sleep difficulties (80 percent)

Where can I find support and resources?

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.”

Sources and References

The content in this guide comes from published studies about RFX3-related syndrome.

  • Harris, H. K., Nakayama, T., Lai, J., Zhao, B., Argyrou, N., Gubbels, C. S., Soucy, A., Genetti, C. A., Suslovitch, V., … & Yu, T. W. (2021). Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior. Genetics in Medicine, 23(6), 1028-1040. https://pubmed.ncbi.nlm.nih.gov/33658631/
  • Torio, M., Maeda, K., Akamine, S., Kawakami, S., Matsubara, Y., Miya, F., Kato, M., & Kira, R. (2023). A case of infantile epileptic spasms syndrome and autism spectrum disorder with an RFX3 mutation. Seizure, 112, 11-14. https://pubmed.ncbi.nlm.nih.gov/37717291/

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