GENE GUIDE

CNOT3-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 CNOT3-Related Syndrome.
a doctor sees a patient

CNOT3-related syndrome happens when there are changes to the CNOT3 gene. These changes can keep the gene from working as it should.

Key Role

The CNOT3 gene plays a role in controlling the cell cycle.

Symptoms

Because the CNOT3 gene is important in brain development and function, many people who have CNOT3-related syndrome have:

  • Global developmental delay
  • Intellectual disability
  • Autism
  • Seizures
  • Speech delay
  • Low muscle tone or hypotonia
  • Heart issues
  • Kidney issues
  • Hearing loss
  • Vision issues
  • Curvature of the spine or scoliosis
  • Frequent infections
  • Joint hypermobility
  • Abnormal brain imaging

CNOT3-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 CNOT3 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 CNOT3 plays a key role in development, de novo variants in this gene can have a meaningful effect.

Research shows that CNOT3-related syndrome is often the result of a de novo variant in CNOT3. Many parents who have had their genes tested do not have the CNOT3 genetic variant found in their child who has the syndrome. In some cases, CNOT3-related syndrome happens because the genetic variant was passed down from a parent.

Autosomal dominant conditions

CNOT3-related syndrome is an autosomal dominant genetic condition. This means that when a person has the one damaging variant in CNOT3 they will likely have symptoms of CNOT3-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 CNOT3 gene?

No parent causes their child’s CNOT3-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 CNOT3-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 CNOT3-related syndrome, the sibling’s risk of having a child who has CNOT3-related syndrome depends on the sibling’s genes and their parents’ genes.

  • If neither parent has the same genetic variant causing CNOT3-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit CNOT3-related syndrome.

As of 2024, at least 38 people with CNOT3-related syndrome have been identified in a medical clinic. The oldest person reported in research publications was 55 years old. The first case of CNOT3-related syndrome was described in 2017.

People who have CNOT3-related syndrome may look different. Appearance can vary and can include some but not all of these features:

  • Noticeable forehead
  • Triangular face
  • Broad nose
  • Deep-set eyes

Scientists and doctors have only just begun to study CNOT3-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 CNOT3-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 a major published article. It highlights how many people have different symptoms. To learn more about the article, see the Sources and references section of this guide.

Speech and Learning

Almost all people with CNOT3-related syndrome had speech delay and developmental delay, although not everyone had intellectual disability.

  • 23 out of 24 people had speech delay (96 percent)
  • 25 out of 25 people had developmental delay (100 percent)
  • 13 out of 18 people had intellectual disability (72 percent)

 

96%
23 out of 24 people had speech delay.
100%
25 out of 25 people had developmental delay.
72%
13 out of 18 people had intellectual disability.

Behavior

Many people with CNOT3-related syndrome had behavioral issues, such as autism or pervasive developmental disorder.

  • 15 out of 25 people had behavioral issues (60 percent)

Brain

Some people with CNOT3-related syndrome had seizures or an abnormal electroencephalogram (EEG). More than one-half of people had brain changes seen on magnetic resonance imaging (MRI) and lower than average muscle tone.

  • 5 out of 24 people had seizures (21 percent)
  • 7 out of 23 people had an abnormal EEG (30 percent)
  • 11 out of 17 people had brain changes on MRI (65 percent)
  • 13 out of 23 people had low muscle tone or hypotonia (57 percent)
Human head showing brain outline
21%
5 out of 24 people had seizures.
30%
7 out of 23 people had an abnormal EEG.
65%
11 out of 17 people had brain changes on MRI.
57%
13 out of 23 people had low muscle tone or hypotonia.

Heart

Some people with CNOT3-related syndrome had heart issues, such as having a hole in the heart.

  • 5 out of 10 people had heart issues (50 percent)

Hearing and vision

Some people with CNOT3-related syndrome had hearing and/or vision issues like conductive hearing loss; crossed eyes (strabismus, esotropia); repetitive, uncontrolled eye movements (nystagmus); and other issues.

  • 13 out of 24 people had hearing and/or vision issues (54 percent)

Mobility

The average age of walking was 25 months, with some children starting as young as 14 months and as late as 55 months. Many people had lower than average muscle tone.

  • 10 out of 16 people had low muscle tone (63 percent)

Growth

People with CNOT3-related syndrome tended to be shorter than average, with a head size that was smaller than average.

  • 13 out of 16 people were shorter than average (81 percent)
  • 13 out of 16 people had a smaller than average head size (81 percent)

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 a published study about CNOT3-related syndrome. Below you can find details about the study, as well as a link to a summary.

  • Zhao, P., Meng, Q., Wan, C., Lei, T., Zhang, L., Zhang, X., Tan, L., Zhu, H., & He, X. (2023). Clinical features of CNOT3-associated neurodevelopmental disorder in three Chinese patients. Neurogenetics, 24(2), 129-136. https://pubmed.ncbi.nlm.nih.gov/36802310/
  • Martin, R., Splitt, M., Genevieve, D., Aten, E., Collins, A., de Bie, C. I., Faivre, L., Foulds, N., Giltay, J., … van Haeringen, A. (2019). De novo variants in CNOT3 cause a variable neurodevelopmental disorder. European Journal of Human Genetics, 27(11), 1677-1682. https://pubmed.ncbi.nlm.nih.gov/31201375/
  • Meyer, R., Begemann, M., Demuth, S., Kraft, F., Dey, D., Schüler, H., Busse, S., Häusler, M., Zerres, K., … Elbracht, M. (2020). Inherited cases of CNOT3-associated intellectual developmental disorder with speech delay, autism, and dysmorphic facies. Clinical Genetics, 98(4), 408-412. https://pubmed.ncbi.nlm.nih.gov/32720325/
  • Lv, J., Ming, W. J., Zheng, Y., Xu, S., Fang, G. L., Zhang, Q., Ding, Y., & Ding, M. P. (2023). A novel pathogenic variant in CNOT3 causing neurodevelopmental delay and epilepsy. Seizure, 107, 104-106. doi:10.1016/j.seizure.2023.03.022

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