GENE GUIDE

ANK3-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 ANK3-Related Syndrome.
a doctor sees a patient

ANK3-related syndrome is also called intellectual developmental disorder, autosomal recessive 37. For this webpage, we will be using the name ANK3-related syndrome to encompass the wide range of variants observed in the people identified.

ANK3related syndrome happens when there are genetic variants in both copies of the ANK3 gene or one loss of function variant in this gene. These variants can keep the gene from working as it should, and they can lead to brain development or function issues.

Key Role

The ANK3 gene plays a role in cell-to-cell contact, division, and movement.

Symptoms

Because the ANK3 gene is important in brain development and function, many people who have ANK3-related syndrome have:

  • Developmental delay
  • Intellectual disability
  • Sleep issues
  • Seizures
  • Lower than average muscle tone
  • Aggressive behavior

ANK3-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 ANK3 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 ANK3 plays a key role in development, de novo variants in this gene can have a meaningful effect. 

Research shows that ANK3-related syndrome is often the result of a de novo variant in ANK3. Many parents who have had their genes tested do not have the ANK3 genetic variant found in their child who has the syndrome. In some cases, ANK3-related syndrome happens because the genetic variant was passed down from a parent.

Some people have variants to their genes that prevent them from working properly. A variant in one copy of the ANK3 gene has little or no effect on their health — because one working copy is enough. People who have one working copy of the gene and one non-working copy of the gene are called ‘carriers’. Some people have genes where both copies do not work as they should. In these cases, the person has inherited non-working copies of the gene from both parents. This can lead to physical issues, developmental issues, or both.

Autosomal dominant conditions

ANK3-related syndrome is an autosomal dominant genetic condition. This means that when a person has the one damaging variant in ANK3 they will likely have symptoms of ANK3-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 recessive conditions

ANK3-related syndrome can also be an autosomal recessive genetic condition. To be affected with symptoms of an autosomal recessive genetic condition, a person has two damaging variants on both copies of their ANK3. For someone with an autosomal recessive genetic syndrome, every time they have a child they will pass on one non-working copy of ANK3.

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

Autosomal Recessive Genetic Syndrome

GENE / gene
Carrier
father
GENE / gene
Carrier
mother
gene / gene
Non-carrier child
GENE / gene
Carrier of the variant
GENE / gene
Carrier of the variant
GENE / GENE
Child with autosomal recessive condition

Why does my child have a change in the ANK3 gene?

No parent causes their child’s de novo gene change. 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.

Autosomal dominant conditions

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 a gene change in ANK3 depends on the genes of both birth parents.

  • If neither birth parent has the same gene change found in their child, the chance of having another child who has the gene change 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 change in the gene.
  • If one birth parent has the same gene change found in their child, the chance of having another child who has the gene change is 50 percent.

For a symptom-free sibling, a brother or sister, of someone who has a gene change in ANK3, the risk of having a child who has a similar gene change depends on the symptom- free sibling’s genes and their parents’ genes.

  • If neither parent has the same change to ANK3 found in their child who has the gene change, the symptom-free sibling has a nearly 0 percent chance of having a child who has the gene change.
  • If one birth parent has the same gene change found in their child who has the gene change, the symptom-free sibling has a small chance of also having the same gene change. If the symptom-free sibling has the same gene change as their sibling who has the gene change, the symptom-free sibling’s chance of having a child who has a similar gene change is 50 percent.

For a person who has a gene change in ANK3, the risk of having a child who has a similar gene change is about 50 percent.

Autosomal recessive conditions

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 the same biological parents to a child with an autosomal recessive genetic condition, having another child who has GENE-related syndrome is almost always 25 percent.
  • The chance of two carrier parents having a child who is also a carrier is 50 percent. Carriers are not expected to have symptoms. 
  • The chance of them having a child who is not a carrier at all is 25 percent.

For a person who has GENE-related syndrome, the risk of having a child who has the same syndrome depends on their partner. 

  • If their partner is a carrier, they have a 50 percent chance of having a child who has the syndrome and a 50 percent chance of having a child who is a carrier. 

If their partner is not a carrier, they have nearly a 0 percent chance of having a child who has the syndrome and a 100 percent chance of having a child who is a carrier.

As of 2024, at least 20 people with ANK3-related syndrome have been described in medical research.

It is unknown whether people with ANK3-related syndrome look different.

Scientists and doctors have only just begun to study people who have changes in the ANK3 gene. At this point, there are no medicines designed to treat the condition. 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
  • Developmental 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 people who have autism 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: 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.

Researchers are now finding that genetic variants in ANK3 associated with autism can be caused by one loss of function ANK3 variant or two ANK3 genetic variants.

Below, we have summarized the medical features identified for these two neurodevelopmental conditions.

Some genetic variants in ANK3 are associated with heart conditions, such as arrhythmogenic cardiomyopathy or Brugada syndrome.

Speech and Learning

All people with ANK3 genetic variants had developmental delay or intellectual disability and speech delay.

  • 13 out of 13 people had developmental delay or intellectual disability (100 percent)
  • 11 out of 11 people had language delay (100 percent)

Behavior

Some people with ANK3-related syndrome caused by a loss of function variant had features of autism, attention deficit hyperactivity disorder, or ADHD, and aggression.

  • 5 out of 7 people had features of autism (71 percent)
  • 2 out of 7 people had ADHD (29 percent)
  • 2 out of 7 people had aggression (29 percent)
71%
5 out of 7 people had features of autism.
29%
2 out of 7 people had ADHD.
29%
2 out of 7 people had agression.

Some people with two ANK3 genetic variants also had hyperactivity and aggressive behavior.

  • 3 out of 4 people had ADHD (75 percent)
  • 4 out of 4 people had aggression (100 percent)

Brain

Some people with ANK3-related syndrome had seizures in infancy or childhood; either a larger than average head size, called macrocephaly, or a smaller than average head size, called microcephaly; and brain changes seen on magnetic resonance imaging (MRI).

  • 4 out of 11 people had seizures (36 percent)
  • 2 out of 9 people had larger than average head size (22 percent)
  • 4 out of 9 people had smaller than average head size (44 percent)
  • 3 out of 7 people had brain changes on MRI (43 percent)
Human head showing brain outline

Mobility

People who have ANK3-related syndrome had movement issues and lower than average muscle tone. Movement issues included spasticity, ataxia, and stereotypic limb movements.

  • 6 out of 11 people had a movement disorder (55 percent)
  • 8 out of 11 people had low muscle tone (73 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.”

Learn more about Simons Searchlight

www.simonssearchlight.org/frequently-asked-questions

Simons Searchlight webpage with more information on ANK3

www.simonssearchlight.org/research/what-we-study/ank3

Simons Searchlight Facebook page for ANK3

www.facebook.com/groups/357567501847117

Sources and References

The information in this guide comes from published studies about people who have autism and who have de novo gene changes in ANK3. Below you can find details about each study, as well as links to summaries, or in some cases the full article.

  • Smith KR. et al. Neuron, 84, 399-415, (2014). Psychiatric risk factor ANK3/ankyrin-G nanodomains regulate the structure and function of glutamatergic synapseswww.ncbi.nlm.nih.gov/pubmed/25374361
  • Kloth K. et al. European Journal of Medical Genetics, 60, 494-498, (2017). First de novo ANK3 nonsense mutation in a boy with intellectual disability, speech impairment and autistic features www.ncbi.nlm.nih.gov/pubmed/28687526
  • Fang, X., Fee, T., Davis, J., Stolerman, E. S., & Caylor, R. C. (2023). Clinical case report: Mosaic ANK3 pathogenic variant in a patient with autism spectrum disorder and neurodevelopmental delay. Cold Spring Harbor Molecular Case Studies, 9(3), a006233. https://pubmed.ncbi.nlm.nih.gov/37263801/
  • Hu, H., Kahrizi, K., Musante, L., Fattahi, Z., Herwig, R., Hosseini, M., Oppitz, C., Abedini, S. S., Suckow, V., … Najmabadi, H. (2019). Genetics of intellectual disability in consanguineous families. Molecular Psychiatry, 24(7), 1027-1039. https://pubmed.ncbi.nlm.nih.gov/29302074/
  • Iqbal, Z., Vandeweyer, G., van der Voet, M., Waryah, A. M., Zahoor, M. Y., Besseling, J. A., Roca, L. T., Vulto-van Silfhout, A. T., Nijhof, B., … Rooms, L. (2013). Homozygous and heterozygous disruptions of ANK3: At the crossroads of neurodevelopmental and psychiatric disorders. Human Molecular Genetics, 22(10), 1960-1970. https://pubmed.ncbi.nlm.nih.gov/23390136/
  • Kloth, K., Lozic, B., Tagoe, J., Hoffer, M. J. V., Van der Ven, A., Thiele, H., Altmüller, J., Kubisch, C., Au, P. Y. B., … Lessel, D. (2021). ANK3 related neurodevelopmental disorders: Expanding the spectrum of heterozygous loss-of-function variants. Neurogenetics, 22(4), 263-269. https://pubmed.ncbi.nlm.nih.gov/34218362/
  • Younus, M., Rasheed, M., Lin, Z., Asiri, S. A., Almazni, I. A., Alshehri, M. A., Shafiq, S., Iqbal, I., Khan, A., … Waqas, A. (2023). Homozygous missense variant in the N-terminal region of ANK3 gene is associated with developmental delay, seizures, speech abnormality, and aggressive behavior. Molecular Syndromology, 14(1), 11-20. https://pubmed.ncbi.nlm.nih.gov/36777705/

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