GENE GUIDE

CUL3-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 2019. 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 CUL3-Related Syndrome.
a doctor sees a patient

CUL3-related syndrome is also called CUL3-related neurodevelopmental disorder. For this webpage, we will be using the name CUL3-related syndrome to encompass the wide range of variants observed in the people identified. 

CUL3-related syndrome happens when there are changes in the CUL3 gene. These changes can keep the gene from working as it should. 

Changes in the CUL3 gene can also cause another condition called pseudohypoaldosteronism type 2E (PHA2E) or Gordon syndrome. 

Genetic variants that cause PHA2E occur in specific regions of CUL3 called intron 8, exon 9, and intron 9. Genetic variants that cause CUL3-related syndrome are thought to occur in other regions of the gene. 

The information below covers CUL3 genetic variants that lead to a neurodevelopmental disorder.

Key Role

The CUL3 gene is involved in several developmental processes in the body, including regulation of the cell cycle, response to stress, cell-to-cell communication, DNA replication, and the circadian rhythm. 

Symptoms

Because the CUL3 gene is important for brain activity, many people who have CUL3-related syndrome have: 

  • Heart defects 
  • Difficulty feeding 
  • Global development delay 
  • Intellectual disability 
  • Speech difficulty 
  • Issues with walking 
  • Seizures 
  • Autism 
  • Brain changes seen on magnetic resonance imaging (MRI)

CUL3-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 CUL3 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 CUL3 plays a key role in development, de novo variants in this gene can have a meaningful effect.

Research shows that CUL3-related syndrome is often the result of a de novo variant in CUL3. Many parents who have had their genes tested do not have the CUL3 genetic variant found in their child who has the syndrome. In some cases, CUL3-related syndrome happens because the genetic variant was passed down from a parent.

Autosomal dominant conditions

CUL3-related syndrome is an autosomal dominant genetic condition. This means that when a person has the one damaging variant in CUL3 they will likely have symptoms of CUL3-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 CUL3 gene?

No parent causes their child’s CUL3-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 CUL3-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 CUL3-related syndrome, the sibling’s risk of having a child who has CUL3-related syndrome depends on the sibling’s genes and their parents’ genes.

  • If neither parent has the same genetic variant causing CUL3-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit CUL3-related syndrome.

As of 2024, over 30 people with CUL3-related syndrome have been described in medical research. Only a few people have been described in detail.

People who have CUL3-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 CUL3-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 CUL3-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 and the Simons Searchlight quarterly registry report. 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 

Many people with CUL3-related syndrome had developmental delay or intellectual disability, and speech issues. 

  • 13 out of 19 people had developmental delay or intellectual disability (68 percent) 
  • 16 out of 19 people had speech issues (84 percent) 

Behavior 

Behavioral issues occurred in people with CUL3-related syndrome, including autism spectrum disorder and attention-deficit/hyperactivity disorder (ADHD). 

  • 13 out of 19 people had autism spectrum disorder (68 percent)
  • 6 out of 19 people had ADHD (32 percent)
68%
13 out of 19 people had autism spectrum disorder.
32%
6 out of 19 people had ADHD.

Brain 

 Few people with CUL3-related syndrome had seizures, whereas almost one-half of people had lower than average muscle tone (hypotonia). 

  • 2 out of 19 people had seizures (11 percent)
  • 8 out of 19 people had hypotonia (42 percent)
Human head showing brain outline
11%
2 out of 19 people had seizures.
42%
8 out of 19 people had hypotonia.

Digestion issues 

Some people had digestion issues such as constipation, diarrhea, and gastroesophageal reflux disease (GERD).

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 CUL3-related syndrome. Below you can find details about each study, as well as links to summaries or, in some cases, the full article.

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