announcement

Read about Simons Searchlight’s commitment to data privacy and security.

GENE GUIDE

SETD5-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 2026. 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 SETD5-Related Syndrome.
a doctor sees a patient

SETD5-related syndrome is also called intellectual developmental disorder, autosomal dominant 23. For this webpage, we will be using the name SETD5-related syndrome to encompass the wide range of variants observed in the people identified.

SETD5-related syndrome happens when there are changes to the SETD5 gene. These changes can keep the gene from working as it should.

Key Role

The SETD5 gene plays a key role in controlling other genes.

Symptoms

Because the SETD5 gene is important for brain activity, many people who have SETD5-related syndrome have:

  • Developmental delay
  • Intellectual disability
  • Language delay
  • Obsessive-compulsive behavior
  • Features of autism
  • Sideways curve of the spine (scoliosis)
  • Vision issues
  • Low muscle tone
  • Short height
  • Predisposition for a brain blood vessel condition called moyamoya syndrome

SETD5-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 SETD5 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 SETD5 plays a key role in development, de novo variants in this gene can have a meaningful effect. 

Research shows that SETD5-related syndrome is often the result of a de novo variant in SETD5. Many parents who have had their genes tested do not have the SETD5 genetic variant found in their child who has the syndrome. In some cases, SETD5-related syndrome happens because the genetic variant was passed down from a parent.

Autosomal dominant conditions

SETD5-related syndrome is an autosomal dominant genetic condition. This means that when a person has the one damaging variant in SETD5 they will likely have symptoms of SETD5-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 SETD5 gene?

No parent causes their child’s SETD5-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 SETD5-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 SETD5-related syndrome, the sibling’s risk of having a child who has SETD5-related syndrome depends on the sibling’s genes and their parents’ genes. 

  • If neither parent has the same genetic variant causing SETD5-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit SETD5-related syndrome. 
  • If one biological parent has the same genetic variant causing SETD5-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 SETD5-related syndrome, the risk of having a child who has the syndrome is about 50 percent.

As of 2026, about 250 people in the world with SETD5-related syndrome have been identified in a medical clinic. The first case of SETD5-related syndrome was described in 2014. Scientists expect to find more people who have the syndrome as access to genetic testing improves.

People with SETD5-related syndrome may look different. Appearance can vary and can include, but is not limited to, these features:

  • Ear and eye defects
  • Low muscle tone

Scientists and doctors have only just begun to study SETD5-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 SETD5-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.

Learning and Speech

Most people with SETD5-related syndrome had developmental delay and/or intellectual disability, and speech delay or impairment.

  • 64 out of 74 people had developmental delay and/or intellectual disability (87 percent)
  • 30 out of 43 people had speech delay or impairment (70 percent)
87%
64 out of 74 people had developmental delay and/or intellectual disability.
70%
30 out of 43 people had speech delay or impairment.

Behavior

Some people with SETD5-related syndrome had behavioral issues, such as autism or features of autism, attention-deficit/hyperactivity disorder (ADHD), aggressive behavior, anxiety, and oppositional behaviors.

  • 23 out of 72 people had features of autism (32 percent)
  • 4 out of 28 people had ADHD (14 percent)
  • 6 out of 28 people had behavioral challenges (21 percent)
  • 3 out of 28 people had anxiety (11 percent)

Graphs

 
 
 
 

100%

80%

60%

40%

20%

0

Autism
ADHD
Behavioral challenges
Anxiety

Brain

People with SETD5-related syndrome had low muscle tone (hypotonia), seizures,  impaired walking or movement issues, sleep diagnoses, and brain changes seen on magnetic resonance imaging (MRI). One-half of people had mild and unspecific cerebral defects.

  • 30 out of 73 people had hypotonia (41 percent)
  • 14 out of 70 people had seizures (20 percent)
  • 11 out of 29 people had impaired walking (38 percent)
  • 5 out of 28 people had a sleep diagnosis (18 percent)
  • 8 out of 15 people had brain changes seen on MRI (53 percent)
Human head showing brain outline

Graphs

 
 
 
 
 

100%

80%

60%

40%

20%

0

Hypotonia
Seizures
Impaired walking
Sleep diagnosis
Brain changes seen on MRI

Development

People with SETD5-related syndrome were short in height, had vision and gastrointestinal issues, and were born with heart defects.

  • 19 out of 46 people had heart defects (41 percent)

Where can I find support and resources?

The SETD5 Syndrome Companion

This site is a free resource hub built for exactly that, by a SETD5 Syndrome parent, for families like ours.

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 SETD5-related syndrome. Below you can find details about each study, as well as links to summaries or, in some cases, the full article.

  • De Falco, A., De Dominicis, A., Trivisano, M., Specchio, N., Digilio, M. C., Piscopo, C., Capra, V., Scala, M., Iacomino, M., … & Terrone, G. (2025). Neurological and psychiatric phenotype of a multicenter cohort of patients with SETD5-related neurodevelopmental disorder. European Journal of Paediatric Neurology, 54, 8-17. doi:10.1016/j.ejpn.2024.11.008
  • Fan, J., Sun, H., Jiang, H., Zhang, S., Xia, H., & He, Y. (2025). A case of a fetus with SETD5 mutation: Prenatal phenotype and literature review. Birth Defects Research, 117(12), e70003. doi:10.1002/bdr2.70003
  • Fernandes, I. R., Cruz, A. C. P., Ferrasa, A., Phan, D., Herai, R. H., & Muotri, A. R. (2018). Genetic variations on SETD5 underlying autistic conditions. Developmental Neurobiology, 78(5), 500-518. doi:10.1002/dneu.22584
  • Luppino, G., Wasniewska, M., Pepe, G., Morabito, L. A., Briuglia, S., Moschella, A., Franchina, F., Lugarà, C., Aversa, T., & Corica, D. (2025). Two years of growth hormone therapy in a child with severe short stature due to overlap syndrome with a novel SETD5 gene mutation: Case report and review of the literature. Genes (Basel), 16(8), 859. doi:10.3390/genes16080859

Stay connected with Simons Searchlight

Join our newsletter to receive updates