GENE GUIDE

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

YWHAG-related syndrome is also called developmental and epileptic encephalopathy 56. For this webpage, we will be using the name YWHAG-related syndrome to encompass the wide range of variants observed in the people identified.

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

Key Role

The YWHAG gene plays a role in cell communication.

Symptoms

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

  • Developmental delay
  • Intellectual disability
  • Delayed speech
  • Poor coordination and wide-based walking
  • Autistic features
  • Seizures
  • Anxiety
  • Obsessive-compulsive habits

YWHAG-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 YWHAG 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 YWHAG plays a key role in development, de novo variants in this gene can have a meaningful effect. 

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

Autosomal dominant conditions

YWHAG-related syndrome is an autosomal dominant genetic condition. This means that when a person has the one damaging variant in YWHAG they will likely have symptoms of YWHAG-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

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

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

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

As of 2024, 48 people with YWHAG-related syndrome have been described in medical research. The oldest person included was 67 years old.

People who have YWHAG-related syndrome may look different. People are described as having distinctive facial features, but the features are quite variable.

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

Currently, researchers think that people with truncating variants in YWHAG might have milder medical features than people with certain missense variants in YWHAG. Researchers need to study more people to be sure. The below information includes anyone with a genetic variant in YWHAG.

Speech and Learning

Not all people with YWHAG-related syndrome had developmental delay or intellectual disability or language delay.

  • 36 out of 45 people had developmental delay or intellectual disability (80 percent)
  • 30 out of 36 people had language delay (83 percent)

Of the people diagnosed with intellectual disability:

  • 26 out of 36 had mild or moderate intellectual disability (72 percent)
  • 26 out of 36 had severe intellectual disability (72 percent)

Behavior

Many people with YWHAG-related syndrome had behavioral findings, such as autism, attention-deficit/hyperactivity disorder (ADHD), or aggressive behaviors.

  • 20 out of 30 people had features of autism (67 percent)

Brain

To date, all people with YWHAG-related syndrome had seizures. Seizure onset can occur between 10 months old to 16 years old. Many people had an abnormal electroencephalogram (EEG), and some people had brain changes seen on magnetic resonance imaging (MRI).

  • 48 out of 48 people had seizures (100 percent)
  • 24 out of 32 people had an abnormal EEG (75 percent)
  • 8 out of 39 people had brain changes on MRI (21 percent)
100%
48 out of 48 people had seizures.
75%
24 out of 32 people had an abnormal EEG.
21%
8 out of 39 people had brain changes on MRI.

Only 4 out of 43 people with YWHAG-related syndrome were not taking anti-seizure medication. Seizure control was possible in about one-half of people with one medication or a combination of medications.

Other neurological features found in about one-half of people included tremors, ataxia, and clumsiness (13 out of 24).

  • 8 out of 13 people had tremor (62 percent)
  • 8 out of 13 people had ataxia (62 percent)
  • 7 out of 13 people had clumsiness (54 percent)
Human head showing brain outline

Sleep

Many people had movement and jerking during sleep that were not thought to be associated with sleep, or had a sleep disorder. Sleep disorders included fragmented sleep, difficulty falling asleep, or waking at night.

  • 12 out of 23 people had movement and jerking during sleep (52 percent)
  • 9 out of 23 people had sleep disorders (39 percent)
52%
12 out of 23 people had movement and jerking during sleep.
43%
9 out of 23 people had sleep disorders.

Where can I find support and resources?

The YWHAG Research Foundation

The YWHAG Research Foundation seeks to raise awareness and educate the public on the YWHAG genetic mutation, while supporting the families affected by this mutation.

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

  • Cetica, V., Pisano, T., Lesca, G., Marafi, D., Licchetta, L., Riccardi, F., Mei, D., Chung, H. B., Bayat, A., … Guerrini, R. (2024). Clinical and molecular characterization of patients with YWHAG-related epilepsy. Epilepsia, 65(5), 1439-1450. https://pubmed.ncbi.nlm.nih.gov/38491959/

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