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What is CUL3-Related Neurodevelopmental Disorder?

About the CUL3 gene 

CUL3 is not the name of a disease or disorder, but rather it is the name of a gene located on the 2nd chromosome. The CUL3 gene provides instructions that tell the body how to make a protein called Cullin3. This does not refer to the type of protein you eat or need for nutrition, but rather proteins in the cell are functional molecules made from our genes. Cullin3 is important because it helps to control the levels of other proteins in our cells. It does this by marking certain proteins for destruction, which allows the cell to break them down and get rid of them when they are no longer needed. 

Cullin3 is part of a larger group of proteins called Cullin-RING E3 ubiquitin ligases (CRLs), which work together to control many different cellular processes such as cell growth and division, DNA replication and repair, and the cell's response to stress.

Because CUL3 is important for maintaining the proper balance of proteins within our cells, when it is not working as it should, it can lead to issues with normal development and function of the nervous system.   

The following is an image of the CUL3 gene. It shows that there are 16 exons, which are the parts of the gene that contain the instructions needed to make the Cullin3 protein. The exons or coding pieces are labeled as such and the yellow filler are the introns or non-coding regions that span between the exons.

Source: Alamut™️ Visual Plus version 1.6.1

How genetic variants impact the CUL3 gene 

Simply put, genetic variation refers to changes in a DNA sequence that make up a gene. This affects how the gene works, and can impact susceptibility to disease. Molecular genetic testing involves determining the clinical significance of variations in a DNA sequence, and variants are classified according to whether or not they are thought to cause disease.


In the case of CUL3, gene variants considered 'pathogenic' or 'likely pathogenic' refer to a change in the gene that are damaging to the function of its protein, and when this happens, can lead to the development of a genetic disorder called CUL3-related neurodevelopmental disorder (also called ‘neurodevelopmental disorder with or without autism or seizures’ in the medical literature). This is a rare condition that affects the development and function of the brain, leading to effects in multiple developmental domains.  

Changes in the CUL3 gene can also cause another condition called Pseudohypoaldosteronism Type 2 (also called ‘Gordon’s syndrome’ or 'familial hyperkalemic hypertension' in the medical literature). This is a rare condition that affects regulation of the amount of sodium and potassium in the body. It can be caused by mutations in several different genes; but gene changes that occur in specific regions of CUL3 (intron 8, exon 9, intron 9) cause the subtype Pseudohypoaldosteronism Type 2E. 

The primary focus of this non-profit is CUL3-related neurodevelopmental disorder. 

How CUL3-related neurodevelopmental disorder happens

CUL3-related neurodevelopmental disorder is an autosomal dominant disorder. In most cases, it appears to happen 'de novo', meaning the gene change was not inherited from either parent, but rather occurred spontaneously. It can also be passed down from a parent; an individual affected by CUL3-related neurodevelopmental disorder has a 50% chance of having a child who is also affected by the disorder.

Symptoms of CUL3-related neurodevelopmental disorder 

CUL3-related neurodevelopmental disorder presents with a range of physical and behavioral features that differ from person to person. The severity of symptoms can also vary; while some individuals may experience mild symptoms, others face more severe and complex challenges.

The medical literature has generally described CUL3-related neurodevelopmental disorder as being characterized by: 

  • global developmental delay 

  • intellectual disability


Other features include:

  • Autism spectrum disorder

  • Seizures

  • Failure to thrive

  • Hypotonia

  • Congenital heart defects

  • Brain imaging anomalies

​Due to the rarity of CUL3-related neurodevelopmental disorder and limited available information, we still don't fully understand all the different ways this disorder affects the body and how it looks or presents in individuals.


Anecdotally, families have noted additional symptoms and behaviours that may also be characteristic of CUL3. These need to be elucidated through further study.  

How CUL3-related neurodevelopmental disorder is diagnosed 

CUL3-related neurodevelopmental disorder is diagnosed with genetic testing. Most often, this would be through:  

  • Whole genome sequencing, which looks at all of an individual's DNA

  • Whole exome sequencing, which looks at the specific parts of an individual's DNA, known as exons, that provide instructions for making proteins 

  • A targeted gene panel, which looks at a specific set of genes associated with a particular condition or group of conditions 

In the situation where an individual is the first person in their family with concerns of a genetic disorder (called the "proband"), a trio analysis is often performed when possible. In the case of CUL3, this would involve comparing the DNA of the affected individual with their biological parents to determine whether the condition was inherited or if it occurred de novo.

Consult your physician for more information on what type of testing you had, or if you are concerned about the possibility of a genetic disorder and wish to be tested. 

Treatment of CUL3-related neurodevelopmental disorder 

Currently, there is no cure for CUL3-related neurodevelopmental disorder. Treatment is focused on managing symptoms and providing supportive care based on an individual’s specific needs. This may include, for instance, physiotherapy, occupational therapy, speech therapy, feeding therapy, and medications given to manage seizures or other symptoms.  

The growth and development of a child with CUL3-related neurodevelopmental disorder should be closely monitored by a physician, and periodic psychoeducational assessments should be considered to inform on necessary supports.

Because the long-term effects of CUL3-related neurodevelopmental disorder can vary widely depending on the individual case, it is best to consult with a qualified healthcare provider for more information on the potential outcomes and management of this disorder.

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