NLGN3-Related Syndrome
NLGN3-related syndrome is also called autism susceptibility, X-linked 1. For this webpage, we will be using the name NLGN3-related syndrome to encompass the wide range of variants observed in the people identified.
What is NLGN3-related syndrome?
NLGN3-related syndrome most often happens when there are changes in the NLGN3 gene. These changes can keep the gene from working as it should.
The NLGN3 gene is located on the X chromosome, one of the sex chromosomes, and males usually have the condition. Only 1 out of 4 people with the condition are female.
Key Role
The NLGN3 gene plays an important role in the interactions between brain cells.
Symptoms
Because the NLGN3 gene is important for the brain, some people may have:
- Developmental delay
- Intellectual disability
- Autism
- Seizures
- Schizophrenia
What causes NLGN3-related syndrome?
NLGN3-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. Genes are arranged in structures in our cells called chromosomes. Chromosomes and genes usually come in pairs, with one copy from the mother, from the egg, and one copy from the father, from the sperm.
We each have 23 pairs of chromosomes. One pair, called the X and Y chromosomes, differs between biological males and biological females. Biological females have two copies of the X chromosome and all its genes, one inherited from their mother and one inherited from their father. Biological males have one copy of the X chromosome and all its genes, inherited from their mother, and one copy of the Y chromosome and its genes, inherited from their father.
In most cases, parents pass on exact copies of the gene to their child. But the process of making the sperm and egg is not perfect. A variant in the genetic code can lead to physical issues, developmental issues, or both.
The NLGN3 gene is located on the X chromosome, so variants in this gene can affect biological males and biological females in different ways. Biological males who have variants in this gene will likely have NLGN3-related syndrome.
Biological females who have variants in this gene may or may not have symptoms of NLGN3-related syndrome. Biological females who have one working copy of the gene and one non-working copy are considered to be ‘carriers’. Even if a biological female does not have signs or symptoms of the syndrome, they can pass it along to their children.
X-linked dominant conditions
NLGN3-related syndrome may result from a spontaneous variant in the NLGN3 gene in the sperm or egg during development. When a brand new genetic variant happens in the genetic code it is called a ‘de novo’ genetic variant. The child can be the first in the family to have the gene 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 NLGN3 plays a key role in development, de novo variants in this gene can have a meaningful effect.
X-Linked Dominant Genetic Syndrome
What causes NLGN3-related syndrome?
X-linked recessive conditions
Research shows that NLGN3-related syndrome can be the result of an inherited variant in NLGN3. This means that NLGN3-related syndrome happens because the genetic variant was passed down from a biological female parent. Biological females that carry the NLGN3 variant usually do not have symptoms, but sometimes they might.
X-Linked Recessive Genetic Syndrome
Why does my child have a change in the NLGN3 gene?
No parent causes their child’s NLGN3-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 of future children will have NLGN3-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 NLGN3-related syndrome depends on the genes of both biological parents.
- Biological females who have a variant in the NLGN3 gene and are pregnant with a daughter have a 50 percent chance of passing on the same genetic variant and a 50 percent chance of passing on the working copy of the gene.
- If they are pregnant with a son, the child has a 50 percent chance of inheriting the genetic variant and the syndrome.
For a symptom-free brother or sister of someone who has NLGN3-related syndrome, the sibling’s risk of having a child who has NLGN3-related syndrome depends on the sibling’s genes and their parents’ genes.
- If neither parent has the same genetic variant causing NLGN3-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit NLGN3-related syndrome.
- If the biological mother has the same genetic variant causing NLGN3-related syndrome, and the symptom-free daughter has the variant, the symptom-free daughter’s chance of having a son who has NLGN3-related syndrome is 50 percent.
For a person who has NLGN3-related syndrome, the risk of having a child who has the syndrome is about 50 percent.
How many people have NLGN3-related syndrome?
As of 2025, at least 38 people in the world with NLGN3-related syndrome have been described in medical research.
Do people who have NLGN3-related syndrome look different?
People who have NLGN3-related syndrome do not look different.
How is NLGN3-related syndrome treated?
Scientists and doctors have only just begun to study NLGN3-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 NLGN3-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: epilepsy.com/…t-is-epilepsy/seizure-types
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 NLGN3-related syndrome
Learning
People with NLGN3-related syndrome had developmental delay or intellectual disability.
- 34 out of 34 people had developmental delay or intellectual disability (100 percent)
Behavior
People with NLGN3-related syndrome had behavioral issues, such as features of autism, anxiety, or sleep issues.
- 34 out of 36 people had features of autism (94 percent)
Brain
Some people with NLGN3-related syndrome had neurological medical issues, including seizures.
Medical and physical concerns linked to NLGN3-related syndrome
Although there have been many people reported in medical research, most studies do not include many medical details.
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 NLGN3: www.simonssearchlight.org/research/what-we-study/nlgn4x
- Simons Searchlight Facebook group: https://www.facebook.com/groups/nlgn3
Sources and References
- Jamain, S., Quach, H., Betancur, C., Råstam, M., Colineaux, C., Gillberg, I. C., Soderstrom, H., Giros, B., Leboyer, M., … & Bourgeron, T. (2003). Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nature Genetics, 34(1), 27-29. doi:10.1038/ng1136
- Hegde, R., Hegde, S., Kulkarni, S. S., Pandurangi, A., Gai, P. B., & Das, K. K. (2021). Genetic analysis of the postsynaptic transmembrane X-linked neuroligin 3 gene in autism. Genomics & Informatics, 19(4), e44. doi:10.5808/gi.21029
- Lehr, A. W., McDaniel, K. F., & Roche, K. W. (2024). Analyses of human genetic data to identify clinically relevant domains of neuroligins. Genes (Basel), 15(12), 1601. doi:10.3390/genes15121601
- Oleari, R., Lettieri, A., Manzini, S., Paganoni, A., André, V., Grazioli, P., Busnelli, M., Duminuco, P., Vitobello, A., … & Cariboni, A. (2023). Autism-linked NLGN3 is a key regulator of gonadotropin-releasing hormone deficiency. Disease Models & Mechanisms, 16(3). doi:10.1242/dmm.049996
- Quartier, A., Courraud, J., Thi Ha, T., McGillivray, G., Isidor, B., Rose, K., Drouot, N., Savidan, M. A., Feger, C., … & Piton, A. (2019). Novel mutations in NLGN3 causing autism spectrum disorder and cognitive impairment. Human Mutation, 40(11), 2021-2032. doi:10.1002/humu.23836
- Xu, X., Xiong, Z., Zhang, L., Liu, Y., Lu, L., Peng, Y., Guo, H., Zhao, J., Xia, K., & Hu, Z. (2014). Variations analysis of NLGN3 and NLGN4X gene in Chinese autism patients. Molecular Biology Reports, 41(6), 4133-4140. doi:10.1007/s11033-014-3284-5