GENE GUIDE

ATRX-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 ATRX-Related Syndrome.
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ATRX-related syndrome is also called alpha thalassemia X-linked intellectual disability syndrome, ATR-X syndrome, and intellectual disability-hypotonic facies syndrome, X-linked. For this webpage, we will be using the name ATRX-related syndrome to encompass the wide range of variants observed in the people identified.

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

Key Role

The ATRX gene helps to keep the cell’s genetic material intact.

Symptoms

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

  • Developmental delay, or intellectual disability, or both
  • Low muscle tone
  • Changes in the genitals
  • Blood disorders, including alpha thalassemia, which is a problem in the production of the oxygen-carrying protein, known as hemoglobin, in red blood cells
  • Small penis in males
  • A curve in the spine called kyphoscoliosis
  • Seizures
  • Speech issues
  • Lower than average muscle tone
  • Some males have evidence of alpha thalassemia on blood tests

ATRX-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 ATRX 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 ATRX-related syndrome. 

X-linked recessive conditions

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

Sometimes it results from a spontaneous variant in the ATRX 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.

Biological females who have variants in this gene may or may not have symptoms of ATRX-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 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 ATRX gene?

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

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

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

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

As of 2024, about 151 people with ATRX-related syndrome have been identified in a medical clinic.

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

  • Smaller than average head size
  • Small ears and nose
  • Widely spaced eyes
  • Protruding tongue
  • Widely spaced top front teeth
  • Large lips
  • Shorter than average height

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

Females have two X chromosomes and two copies of the ATRX gene. Females carrying a pathogenic or likely pathogenic ATRX variant rarely have medical features.

Usually, the X chromosome carrying the variant undergoes selective X inactivation. This is a random process where a cell chooses one X chromosome to silence gene expression. If the affected X chromosome is inactivated, this means that the ATRX variant would be silenced or turned off. For some females, the unaffected X chromosome is inactivated, resulting in a person having more medical features.

The information below includes mostly males with ATRX-related syndrome.

Some studies have suggested that there is a link between where a variant occurs in the ATRX gene and the type of medical features a person develops.

Pathogenic variants in the amino acid region 170 to 272 (the ATRX zinc finger domain) may result in severe psychomotor impairment and urogenital defects.

Pathogenic variants in the helicase domains, amino acid region 1581 to 1768, or amino acid region 2025 to 2205, result in milder medical issues.

More severe genital defects occur with variants in the PHD-type domain (amino acid region 217 to 272).

Finally, variant p.Arg37* is a reoccurring variant that results in milder medical issues overall.

Speech and Learning

All people with ATRX-related syndrome had developmental delay or intellectual disability, and some people had language delays or impairment. Intellectual disability varied from mild to profound.

  • 100 percent of people had developmental delay or intellectual disability

Brain

Less than one-half of people with ATRX-related syndrome had seizures. The majority of people had a smaller than average head size at birth, also called microcephaly, and a lower than average muscle tone, also called hypotonia.

  • 30 to 40 percent of people had seizures
  • 75 to 85 percent of people had microcephaly
  • 80 to 90 percent of people had hypotonia

Other medical features

Most people had gastrointestinal issues, such as feeding difficulty, vomiting, reflux, abdominal distention, pain, and constipation. Males tended to have genital defects, including undescended testicles, abnormal positioning of the urethral opening, genitals that might not look clearly like male or female, or female-appearing genitals. People with ATRX-related syndrome were usually short in height, and this feature was present at birth.

 

  • 70 to 80 percent of people had gastrointestinal issues
  • 70 to 80 percent of people had genital defects
  • 60 to 70 percent of people had short height

Some variants in ATRX can develop spontaneously after a person’s birth, in any cells of the body. These type of variants are called somatic variants. Somatic ATRX variants are associated with cancer.

It is not clear if people with ATRX-related syndrome are predisposed to tumor development. More research is needed. There have been four children with ATRX-related syndrome who have been diagnosed with a bone cancer.

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 ATRX-related syndrome. Below you can find details about the study, as well as a link to the full article.

  • Badens, C., Martini, N., Courrier, S., DesPortes, V., Touraine, R., Levy, N., & Edery, P. (2006). ATRX syndrome in a girl with a heterozygous mutation in the ATRX Zn finger domain and a totally skewed X-inactivation pattern. American Journal of Medical Genetics Part A, 140(20), 2212-2215. https://pubmed.ncbi.nlm.nih.gov/16955409/
  • Stevenson, R. E. Alpha-thalassemia X-linked intellectual disability syndrome. 2020 May 28. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1449/

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