DLG4-Related Syndrome
DLG4-related syndrome is also called sleep disturbances, hypotonia, intellectual disability, neurologic disorder, and epilepsy (SHINE) syndrome, DLG4 synaptopathy, or intellectual developmental disorder, autosomal dominant 62. For this webpage, we will be using the name DLG4-related syndrome to encompass the wide range of variants observed in the people identified.
What is DLG4-related syndrome?
DLG4-related syndrome happens when there are changes in the DLG4 gene. These changes can keep the gene from working as it should.
Key Role
The DLG4 gene contains the instructions for making a protein called PSD-95. The PSD-95 protein plays a key role in communication between brain cells. This communication happens in the spaces between brain cells called synapses.
Symptoms
Because the DLG4 gene is important for brain activity, many people who have DLG4-related syndrome have:
- Developmental delays in early childhood
- Intellectual disability
- Seizures
- Autism spectrum disorder
- Behavioral issues
- Eye and vision issues
- Low muscle tone
- Sleep challenges
- Brain changes seen on magnetic resonance imaging (MRI)
What causes DLG4-related syndrome?
DLG4-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 DLG4 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 DLG4 plays a key role in development, de novo variants in this gene can have a meaningful effect.
Research shows that DLG4-related syndrome is often the result of a de novo variant in DLG4. Many parents who have had their genes tested do not have the DLG4 genetic variant found in their child who has the syndrome. In some cases, DLG4-related syndrome happens because the genetic variant was passed down from a parent.
Autosomal dominant conditions
DLG4-related syndrome is an autosomal dominant genetic condition. This means that when a person has the one damaging variant in DLG4 they will likely have symptoms of DLG4-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
Why does my child have a change in the DLG4 gene?
No parent causes their child’s DLG4-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.
What are the chances that other family members or future children will have DLG4-related syndrome?
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 DLG4-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 DLG4-related syndrome, the sibling’s risk of having a child who has DLG4-related syndrome depends on the sibling’s genes and their parents’ genes.
- If neither parent has the same genetic variant causing DLG4-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit DLG4-related syndrome.
- If one biological parent has the same genetic variant causing DLG4-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 DLG4-related syndrome, the risk of having a child who has the syndrome is about 50 percent.
How many people have DLG4-related syndrome?
As of 2026, about 134 people with DLG4-related syndrome have been identified in a medical clinic.
Do people who have DLG4-related syndrome look different?
People who have DLG4-related syndrome may look different, but features are non-specific.
How is DLG4-related syndrome treated?
Scientists and doctors have only just begun to study DLG4-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:
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- 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:
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- Suggest the right therapies. This can include physical, occupational, speech, or behavioral therapy.
- Guide individualized education plans (IEPs).
Specialists advise that therapies for DLG4-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.
Behavior and development concerns linked to HNRNPC-related syndrome
Learning and speech
People with DLG4-related syndrome had developmental delay or intellectual disability, and speech and language impairment. The average age of walking was about 20 months, and the first words were at 32 months.
- 38 out of 45 people had developmental delay (84 percent)
- 45 out of 45 people had intellectual disability (100 percent)
- 30 out of 35 people had language and communication impairment (86 percent)
The severity of intellectual disability (ID) varied among people:
- 10 out of 33 people had mild ID (30 percent)
- 14 out of 33 people had moderate ID (42 percent)
- 8 out of 33 people had severe or profound ID (24 percent)
- 1 out of 33 people had an unknown level of ID (3 percent)
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Behavior
Some people with DLG4-related syndrome had behavioral issues, such as autism, attention-deficit/hyperactivity disorder (ADHD), aggression, anxiety, agitation, and mood disorders.
- 26 out of 36 people had autism or features of autism (72 percent)
- 21 out of 35 people had ADHD (60 percent)
Brain
People with DLG4-related syndrome had neurological medical issues, such as poor muscle control that causes clumsy movements (ataxia), having difficulty performing tasks or movements (apraxia), tremors, a condition with muscle contractions resulting in repetitive movements or postures (dystonia), low muscle tone (hypotonia), and insomnia.
- 12 out of 35 people had ataxia (34 percent)
- 18 out of 33 people had apraxia (55 percent)
- 9 out of 34 people had tremors (27 percent)
- 8 out of 32 people had dystonia (25 percent)
- 22 out of 35 people had hypotonia (63 percent)
- 24 out of 35 people had insomnia (69 percent)
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Many people had seizures, most commonly focal seizures and generalized tonic-clonic seizures. The average age of seizure onset was about 7 years old, with a range of about 3 months to 16 years.
- 25 out of 47 people had seizures (53 percent)
Medical and physical concerns linked to DLG4-related syndrome
Regression
Some people with DLG4-related syndrome had a regression in motor development and/or language. Most people with language regression had autism, but not all people with autism had language regression. Seizures and infection can be associated with developmental regression. The average age of regression was about 4 years.
- 18 out of 44 people had a developmental regression (41 percent)
Development
Some people with DLG4-related syndrome had joint laxity or hypermobile joints, a long face, slender body, and sunken chest (pectus excavatum). Some had episodes of vomiting that were associated with seizures, fatigue, or motion sickness.
- 16 out of 44 people had joint laxity (36 percent)
- 9 out of 38 people had a slender body and sunken chest (24 percent)
- 10 out of 35 people had vomiting (29 percent)
Vision
Many people with DLG4-related syndrome had vision issues, including eyes that move rapidly without control (nystagmus), crossed eyes (strabismus), farsightedness (hyperopia), nearsightedness (myopia), and cortical blindness.
- 23 out of 46 people had vision issues (50 percent)
Where can I find support and resources?
DLG4 SHINE Foundation
The DLG4 SHINE Foundation’s mission is to improve the lives of individuals with DLG4-related Synaptopathy by supporting research, developing treatments and therapies, and providing a community of support. They understand the challenges that families face when dealing with this rare disease, and we are committed to making a difference. By collaborating with researchers, healthcare professionals, and other organizations, they aim to accelerate medical advances focused on the treatment of DLG4 Synaptopathy.
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 DLG4: www.simonssearchlight.org/research/what-we-study/dlg4
- Simons Searchlight DLG4 Facebook community: https://www.facebook.com/groups/dlg4
Sources and References
- Kassabian, B., Levy, A. M., Gardella, E., Aledo-Serrano, A., Ananth, A. L., Brea-Fernández, A. J., Caumes, R., Chatron, N., Dainelli, A., … & Rubboli, G. (2024). Developmental epileptic encephalopathy in DLG4-related synaptopathy. Epilepsia, 65(4), 1029-1045. doi:10.1111/epi.17876
- Tokunaga, S., Shimomura, H., Taniguchi, N., Yanagi, K., Kaname, T., Okamoto, N., & Takeshima, Y. (2024). A novel DLG4 variant causes DLG4-related synaptopathy with intellectual regression. Human Genome Variation, 11(1), 1. doi:10.1038/s41439-023-00260-x
- Tümer, Z., Dye, T. J., Prada, C., White-Brown, A. M., MacKenzie, A., & Levy, A. M. DLG4-related synaptopathy. 2023 Jun 22. In: Adam MP, Bick S, Mirzaa GM, et al., editors. GeneReviews® [Internet] Seattle (WA): University of Washington, Seattle; 1993-2026. Available from: https://www.ncbi.nlm.nih.gov/books/NBK592682/