ITSN1-Related Syndrome
What is ITSN1-related syndrome?
ITSN1-related syndrome happens when there are changes in the ITSN1 gene. These changes can keep the gene from working as it should.
Key Role
The ITSN1 gene plays a key role in the function and communication of brain cells.
Symptoms
Because the ITSN1 gene is important for brain activity, many people who have ITSN1-related syndrome have:
- Developmental delay
- Intellectual disability
- Seizures
- Autism spectrum disorder or features of autism
- Speech impairment
- Low muscle tone
- Vision issues
What causes ITSN1-related syndrome?
ITSN1-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 ITSN1 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 ITSN1 plays a key role in development, de novo variants in this gene can have a meaningful effect.
Research shows that ITSN1-related syndrome is often the result of a de novo variant in ITSN1. Many parents who have had their genes tested do not have the ITSN1 genetic variant found in their child who has the syndrome. In some cases, ITSN1-related syndrome happens because the genetic variant was passed down from a parent.
Autosomal dominant conditions
ITSN1-related syndrome is an autosomal dominant genetic condition. This means that when a person has the one damaging variant in ITSN1 they will likely have symptoms of ITSN1-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
Why does my child have a change in the ITSN1 gene?
No parent causes their child’s ITSN1-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.
What are the chances that other family members or future children will have ITSN1-related syndrome?
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 ITSN1-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 ITSN1-related syndrome, the sibling’s risk of having a child who has ITSN1-related syndrome depends on the sibling’s genes and their parents’ genes.
- If neither parent has the same genetic variant causing ITSN1-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit ITSN1-related syndrome.
- If one biological parent has the same genetic variant causing ITSN1-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 ITSN1-related syndrome, the risk of having a child who has the syndrome is about 50 percent.
How many people have ITSN1-related syndrome?
As of 2026, about 26 people with ITSN1-related syndrome have been identified in a medical clinic.
Do people who have ITSN1-related syndrome look different?
People who have ITSN1-related syndrome might not look very different. Some people have been described as having unique facial features, but there is no common pattern.
How is ITSN1-related syndrome treated?
Scientists and doctors have only just begun to study ITSN1-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:
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- 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:
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- Suggest the right therapies. This can include physical, occupational, speech, or behavioral therapy.
- Guide individualized education plans (IEPs).
Specialists advise that therapies for ITSN1-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.
Behavior and development concerns linked to ITSN1-related syndrome
Learning and Speech
All people with ITSN1-related syndrome had developmental delay or intellectual disability, and speech delay or impairment. Some people had a regression of speech, sometimes leading to a speech arrest. Several people developed an involuntary or unprompted repetition of words (echolalia).
- 11 out of 11 people had developmental delay or intellectual disability (100 percent)
- 11 out of 11 people had speech delay or impairment (100 percent)
- 6 out of 11 people had a speech regression (55 percent)
- 4 out of 6 people had echolalia (67 percent)
Behavior
Almost all people with ITSN1-related syndrome had behavioral issues, such as features of autism, attention-deficit/hyperactivity disorder (ADHD), repetitive behaviors (stereotypic behavior), aggressive outburst and self-mutilation, social impairment, and anxiety. One person had psychosis and one person had schizophrenia.
- 10 out of 11 people had autism (91 percent)
- 5 out of 10 people had ADHD (50 percent)
- 3 out of 10 people had stereotypies (30 percent)
- 2 out of 10 people had aggressive outburst and self-mutilation (20 percent)
- 3 out of 10 people had social impairment (30 percent)
- 2 out of 10 people had anxiety (20 percent)
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Brain
Some people with ITSN1-related syndrome had seizures, brain changes seen on magnetic resonance imaging (MRI), and lower than average muscle tone (hypotonia).
- 3 out of 10 people had seizures (30 percent)
- 1 out of 7 people had brain changes seen on MRI (14 percent)
- 5 out of 10 people had hypotonia (50 percent)
Deletions that include the ITSN1 gene
Some people with ITSN1-related syndrome had a genetic variant called a copy number variant in which they had a section of their DNA missing that included more than the ITSN1 gene. Each person had a different section of missing DNA.
In the medical research, 17 people had a deletion that included the ITSN1 gene, as well as other genes in their copy number variant. The information below summarizes what is known about these 17 people.
Learning
All people with ITSN1-related syndrome that was due to a copy number variant had mild to severe developmental delay or intellectual disability.
- 17 out of 17 people had developmental delay or intellectual disability (100 percent)
Brain
People with ITSN1-related syndrome that was due to a copy number variant had seizures, lower than average muscle tone (hypotonia), a smaller than average head size (microcephaly), and brain changes seen on magnetic resonance imaging (MRI). Most common brain changes included the complete absence (agenesis) and underdevelopment/thinning (hypoplasia) of a brain region called the corpus callosum.
- 6 out of 13 people had seizures (46 percent)
- 9 out of 9 people had hypotonia (100 percent)
- 12 out of 15 people had microcephaly (80 percent)
- 11 out of 15 people had brain changes seen on MRI (73 percent)
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Development
Many people with ITSN1-related syndrome that was due to a copy number variant had changes in development, including growth delay, short height, skeleton changes, heart structure defects, and vision issues, most commonly crossed eyes (strabismus).
- 14 out of 14 people had growth delay (100 percent)
- 10 out of 10 people had short height (100 percent)
- 11 out of 15 people had skeleton changes (73 percent)
- 10 out of 16 people had heart structure defects (63 percent)
- 10 out of 11 people had vision issues (91 percent)
ITSN1 Foundation
The ITSN1 Foundation’s goal is to help families understand what ITSN1 is, connect with ongoing research, and eventually build a supportive community.
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 ITSN1 – www.simonssearchlight.org/research/what-we-study/itsn1
Sources and References
- Bruel, A. L., Vitobello, A., Thiffault, I., Manwaring, L., Willing, M., Agrawal, P. B., Bayat, A., Kitzler, T. M., Brownstein, C. A., … & Faivre, L. (2022). ITSN1: A novel candidate gene involved in autosomal dominant neurodevelopmental disorder spectrum. European Journal of Human Genetics, 30(1), 111-116. doi:10.1038/s41431-021-00985-9
- Fukai, R., Hiraki, Y., Nishimura, G., Nakashima, M., Tsurusaki, Y., Saitsu, H., Matsumoto, N., & Miyake, N. (2014). A de novo 1.4-Mb deletion at 21q22.11 in a boy with developmental delay. American Journal of Medical Genetics Part A, 164A(4), 1021-1028. doi:10.1002/ajmg.a.36377
- Liaqat, K., Treat, K., Wilson, T. E., Conboy, E., & Vetrini, F. (2024). Further evidence of involvement of ITSN1 in autosomal dominant neurodevelopmental disorder. Clinical Genetics, 105(4), 455-456. doi:10.1111/cge.14497