GENE GUIDE

NLGN4X-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 NLGN4X-Related Syndrome.
a doctor sees a patient

NLGN4X-related syndrome is also called autism susceptibility, X-linked 2 and intellectual developmental disorder, X-linked. For this webpage, we will be using the name NLGN4X-related syndrome to encompass the wide range of variants observed in the people identified.

NLGN4X-related syndrome happens when there are changes in the NLGN4X gene. These changes can keep the gene from working as it should.

Key Role

The NLGN4X gene plays a key role in communication between brain cells. 

Symptoms

Because the NLGN4X gene is important for brain activity, many people who have NLGN4X-related syndrome have: 

  • Autism 
  • Intellectual disability 
  • Developmental delay 
  • Speaking impairment and motor speech disorder 
  • Repetitive behaviors 
  • Attention-deficit/hyperactivity disorder (ADHD) 
  • Motor tics

NLGN4X-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 NLGN4X 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 NLGN4X-related syndrome. 

Biological females who have variants in this gene may or may not have symptoms of NLGN4X-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 recessive conditions

Research shows that NLGN4X-related syndrome is often the result of an inherited variant in NLGN4X. This means that NLGN4X-related syndrome happens because the genetic variant was passed down from a biological female parent. Biological females that carry the NLGN4X variant usually do not have symptoms, but sometimes they might. 

Sometimes it results from a spontaneous variant in the NLGN4X gene in the sperm or egg during development. When a brand new genetic variant happens in the genetic code is called a ‘de novo’ genetic variant. The child can be the first in the family to have the gene variant. 

X-Linked Recessive Genetic Syndrome

Sex chromosomes
Non-carrier father
Carrier mother
Sex chromosomes
Non-carrier female
Carrier female
Male child with X-linked
genetic condition
Non-carrier
male

Why does my child have a change in the NLGN4X gene?

No parent causes their child’s NLGN4X-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 NLGN4X-related syndrome depends on the genes of both biological parents. 

  • Biological females who have a variant in the NLGN4X 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 NLGN4X-related syndrome, the sibling’s risk of having a child who has NLGN4X-related syndrome depends on the sibling’s genes and their parents’ genes. 

  • If neither parent has the same genetic variant causing NLGN4X-related syndrome, the symptom-free sibling has a nearly 0 percent chance of having a child who would inherit NLGN4X-related syndrome. 
  • If the biological mother has the same genetic variant causing NLGN4X-related syndrome, and the symptom-free daughter has the variant, the symptom-free daughter’s chance of having a son who has NLGN4X-related syndrome is 50 percent. 

For a person who has NLGN4X-related syndrome, the risk of having a child who has the syndrome is about 50 percent.

As of 2024, over 20 people with NLGN4X-related syndrome have been reported in medical research. 

People who have NLGN4X-related syndrome might not look very different. 

Scientists and doctors have only just begun to study NLGN4X-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 NLGN4X-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.

Some NLGN4X variants were inherited from the mother who may or may not have medical features. Most documented people with NLGN4X-related syndrome were males. The information below includes males and females diagnosed with NLGN4X-related syndrome. 

Learning 

People with NLGN4X-related syndrome had developmental delay or intellectual disability.  

  • 8 out of 27 people had developmental delay or intellectual disability (30 percent)

Behavior 

People with NLGN4X-related syndrome had behavioral issues, including autism, attention-deficit/hyperactivity disorder (ADHD), aggressive behaviors, and anxiety. 

  • 17 out of 28 people had autism (61 percent)
61%
17 out of 28 people had autism.

Other features 

Some people with NLGN4X-related syndrome had lower than average muscle tone, vision issues, cerebral palsy, or Tourette disorder.

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 published studies about NLGN4X-related syndrome.

  • Kopp, N., Amarillo, I., Martinez-Agosto, J., & Quintero-Rivera, F. (2021). Pathogenic paternally inherited NLGN4X deletion in a female with autism spectrum disorder: Clinical, cytogenetic, and molecular characterization. American Journal of Medical Genetics Part A, 185(3), 894-900. https://pubmed.ncbi.nlm.nih.gov/33369065/
  • Nguyen, T. A., Lehr, A. W., & Roche, K. W. (2020). Neuroligins and neurodevelopmental disorders: X-linked genetics. Frontiers in Synaptic Neuroscience, 12, 33. https://pubmed.ncbi.nlm.nih.gov/32848696/

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