GENE GUIDE

ARHGEF9-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 ARHGEF9-Related Syndrome.
a doctor sees a patient

ARHGEF9-related syndrome is also called developmental and epileptic encephalopathy 8. For this webpage, we will be using the name ARHGEF9-related syndrome to encompass the wide range of variants observed in the people identified.

ARHGEF9-related syndrome happens when there are changes in the ARHGEF9 gene. These changes can keep the gene from working as it should.

Key Role

The ARHGEF9 gene plays a key role in the communication that takes place between brain cells.

Symptoms

Because the ARHGEF9 gene is important for brain activity, many people who have ARHGEF9-related syndrome have:

  • Developmental delay
  • Intellectual disability
  • Epilepsy
  • Changes in facial features
  • Brain changes observed on magnetic resonance imaging (MRI)
  • Autism
  • Hyperactivity
  • Impulsivity

ARHGEF9-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. Genes are arranged in structures in our cells called chromosomes. Chromosomes and genes usually come in pairs, with one copy from the mother’s egg, and one copy from the father’s sperm. 

We each have 23 pairs of chromosomes. One pair, called the X and Y chromosomes, differs between biological males and biological females. Biological females have two copies of the X chromosome and all its genes, one inherited from their mother and one inherited from their father. Biological males have one copy of the X chromosome and all its genes, inherited from their mother, and one copy of the Y chromosome and its genes, inherited from their father. 

In most cases, parents pass on exact copies of the gene to their child. But the process of making the sperm and egg is not perfect. A variant in the genetic code can lead to physical issues, developmental issues, or both. 

The ARHGEF9 gene is located on the X chromosome, therefore variants in this gene can affect biological males and biological females in different ways. Biological males who have variants in this gene will likely have ARHGEF9-related syndrome. 

Biological females who have variants in this gene may or may not have symptoms of ARHGEF9-related syndrome. Biological females who have one working copy of the gene and one non-working copy are considered to be ‘carriers’. Even if a biological female does not have signs or symptoms of the syndrome, they can pass it along to their children.

X-linked dominant conditions

ARHGEF9-related syndrome usually results from a spontaneous variant in the ARHGEF9 gene in the sperm or egg during development. When a brand new genetic variant happens in the genetic code it is called a ‘de novo’ genetic variant. The child can be the first in the family to have the gene 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 ARHGEF9 plays a key role in development, de novo variants in this gene can have a meaningful effect. Many parents who have had their genes tested do not have the ARHGEF9 gene variant found in their child who has the syndrome.

In some cases, ARHGEF9-related syndrome is inherited. Biological females who inherit the ARHGEF9 gene variant tend to have milder symptoms than those who have a de novo variant.

X-Linked Recessive Genetic Syndrome

Sex chromosomes
Non-carrier father
Carrier mother
Sex chromosomes
Non-carrier female
Carrier female
Male child with X-linked
genetic condition
Non-carrier
male

Why does my child have a change in the ARHGEF9 gene?

No parent causes their child’s ARHGEF9-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 ARHGEF9-related syndrome depends on the genes of both biological parents. 

  • For a biological female parent who does not have 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 increased 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. 
  • For a biological female parent who has the same ARHGEF9 variant and is pregnant with a daughter, there is a 50 percent chance of passing on the same genetic variant and a 50 percent chance of passing on the working copy of the gene without the same ARHGEF9 genetic variant. 
  • If they are pregnant with a son, there is a 50 percent chance of passing on the same genetic variant and the syndrome.  

For a symptom-free brother or sister of someone who has ARHGEF9-related syndrome, the sibling’s risk of having a child who has ARHGEF9-related syndrome depends on the sibling’s genes and their parents’ genes. 

  • If neither parent has the same genetic variant causing ARHGEF9-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit ARHGEF9-related syndrome.
  • If the biological mother has the same genetic variant causing ARHGEF9-related syndrome, the symptom-free daughter has a 50 percent chance of also having the same genetic variant. If the symptom-free daughter has the same genetic variant as their sibling who has the syndrome, the symptom-free sibling’s chance of having a son who has ARHGEF9-related syndrome is 50 percent. 

For a person who has ARHGEF9-related syndrome, the risk of having a child who has the syndrome is about 50 percent.

As of 2024, about 57 people with ARHGEF9-related syndrome have been identified in a medical clinic.

People who have ARHGEF9-related syndrome might not look very different. Some people have unique facial features, but there is no common pattern.

Scientists and doctors have only just begun to study ARHGEF9-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 ARHGEF9-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.

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.

Females have two X chromosomes and two copies of the ARHGEF9 gene. Females carrying a pathogenic or likely pathogenic ARHGEF9 variant rarely have medical features.

Usually, the X chromosome carrying the variant undergoes selective X inactivation. This is a random process where a cell chooses one X chromosome to silence gene expression. If the affected X chromosome is inactivated, this means that the ARHGEF9 variant would be silenced or turned off. For some females, the unaffected X chromosome is inactivated, resulting in a person having more medical features.

The information below includes about 34 males and 11 females with ARHGEF9-related syndrome. Most female carriers do not have medical features.

Speech and Learning

Many people with ARHGEF9-related syndrome had developmental delay or intellectual disability (ID). Some people had speech delay or were non-verbal.

  • 44 out of 45 people had developmental delay or intellectual disability (98 percent)

For people over the age of 4 years old:

  • 17 out of 29 people had severe ID (59 percent)
  • 9 out of 29 people had moderate ID (31 percent)
  • 3 out of 29 people had mild ID (10 percent)
59%
17 out of 29 people had severe ID.
31%
9 out of 29 people had moderate ID.
10%
3 out of 29 people had mild ID.

Behavior

People with ARHGEF9-related syndrome had behavioral disorders, such as autism, features of autism, hyperactivity, impulsivity, hyperarousal to noise (hyperekplexia), and shyness.

Brain

Most people with ARHGEF9-related syndrome had seizures, and some people had brain changes observed on magnetic resonance imaging (MRI), such as brain atrophy in the cerebral cortex, corpus callosum hypoplasia, and cerebellar vermis.

Seizures usually started around 1 year of age. Seizure types included epileptic encephalopathy and febrile seizures, focal seizures, generalized tonic–clonic seizures, myoclonus, and thermosensitive epilepsy. Some people were able to control seizures with anti-epilepsy medication, but no common medicine worked for all people, and a combination of medications and diet might be needed.

  • 29 out of 34 people had seizures (85 percent)
  • 7 out of 20 people had brain changes on MRI (35 percent)
Human head showing brain outline
85%
29 out of 34 people had seizures.
35%
7 out of 20 people had brain changes on MRI.

Facial features

Research has suggested that people with more severe ID and seizures might have more distinctive facial features. These included enlarged, fleshy earlobes, a sunken appearance of the middle face (midface hypoplasia), and a protruding jaw (prognathism).

Other medical findings

Some people with ARHGEF9-related syndrome had sleep disorders, motor incoordination, or ataxia.

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 ARHGEF9-related syndrome. Below you can find details about each study, as well as links to summaries or, in some cases, the full article.

  • Alber, M., Kalscheuer, V. M., Marco, E., Sherr, E., Lesca, G., Till, M., Gradek, G., Wiesener, A., Korenke, C, … & Minassian, B. A. (2017). ARHGEF9 disease: Phenotype clarification and genotype-phenotype correlation. Neurology Genetics, 3(3),e148. https://pubmed.ncbi.nlm.nih.gov/28589176/
  • Bernardo, P., Cuccurullo, C., Rubino, M., De Vita, G., Terrone, G., Bilo, L., & Coppola, A. (2024). X-linked epilepsies: A narrative review. International Journal of Molecular Sciences, 25(7), 4110. https://pubmed.ncbi.nlm.nih.gov/38612920/
  • Scala, M., Zonneveld-Huijssoon, E., Brienza, M., Mecarelli, O., van der Hout, A. H., Zambrelli, E., Turner, K., Zara, F., Peron, A., … & Striano, P. (2021). De novo ARHGEF9 missense variants associated with neurodevelopmental disorder in females: Expanding the genotypic and phenotypic spectrum of ARHGEF9 disease in females. Neurogenetics, 22(1), 87-94. https://pubmed.ncbi.nlm.nih.gov/32939676/
  • Qiu, T., Dai, Q., & Wang, Q. (2021). A novel de novo hemizygous ARHGEF9 mutation associated with severe intellectual disability and epilepsy: A case report. Journal of International Medical Research, 49(11), 3000605211058372. https://pubmed.ncbi.nlm.nih.gov/34851771/
  • Yang, H., Liao, H., Gan, S., Xiao, T., & Wu, L. (2022). ARHGEF9 gene variant leads to developmental and epileptic encephalopathy: Genotypic phenotype analysis and treatment exploration. Molecular Genetics & Genomic Medicine, 10(7), e1967. https://pubmed.ncbi.nlm.nih.gov/35638461/

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